Thiazolyl-dihydro-quinazoline compounds and processes for preparing same

ABSTRACT

Disclosed are thiazolyl-dihydro-quinazolines of general formula (I) 
     
       
         
         
             
             
         
       
     
     wherein the groups R 1  to R 4  have the meanings given in the claims and specification, the isomers thereof, and processes for preparing these compounds and their use as pharmaceutical compositions.

APPLICATION DATA

This application is a continuation application of U.S. application Ser.No. 11/690,362 filed on Mar. 23, 2007 which claims benefit to EP06112300 filed Apr. 6, 2006.

The present invention relates to new thiazolyl-dihydro-quinazolines ofgeneral formula (I)

wherein X and the groups R¹ to R⁴ have the meanings given in the claimsand specification, the isomers thereof, and processes for preparingthese thiazolyldihydro-quinazolines and their use as pharmaceuticalcompositions.

BACKGROUND TO THE INVENTION

Phosphatidylinositol-3-kinases (PI3-kinases) are a subfamily of thelipid kinases which catalyse the transfer of a phosphate group to the3′-position of the inositol ring of phosphoinositides.

They have a role in numerous cell processes such as e.g. cell growth anddifferentiation processes, the control of cytoskeletal changes and theregulation of intracellular transport processes (Vanhaesebroeck et al.,Annu Rev Biochem. 2001; 70:535-602).

PI3-kinases may play a part in numerous tumours, such as e.g. breastcancer, ovarian or pancreatic carcinoma, in tumour types such ascarcinomas of the colon, breast or lungs, but particularly in autoimmunediseases such as Crohn's disease or rheumatoid arthritis, for example,or in the cardiovascular system, e.g. in the development of cardiachypertrophy (Oudit et al., Circulation. 2003 oct 28; 108(17):2147-52).PI3-kinase modulators may represent a possible method ofanti-inflammatory therapy with comparatively minor side effects (Wardand Finan, Curr Opin Pharmacol. 2003 August; 3(4):426-34).

PI3-kinase inhibitors for treating inflammatory diseases are known inthe literature. Thus, WO 03/072557 discloses 5-phenylthiazolederivatives, WO 04/029055 discloses annelated azolpyrimidines and WO04/007491 discloses azolidinone-vinyl linked benzene derivatives.Moreover, the two specifications WO 04/052373 and WO 04/056820 disclosebenzoxazine and benzoxazin-3-one derivatives.

The aim of the present invention is to provide new compounds which byvirtue of their pharmaceutical activity as PI3-kinase modulators may beused therapeutically for the treatment of inflammatory or allergicdiseases. Examples of these include inflammatory and allergicrespiratory complaints, inflammatory and allergic skin complaints,inflammatory eye diseases, diseases of the nasal mucosa, inflammatory orallergic illnesses which involve autoimmune reactions or kidneyinflammation.

DESCRIPTION OF THE INVENTION

Surprisingly it has been found that the aim outlined above is achievedby means of compounds of formula (I), wherein the groups R¹ to R⁴ havethe meanings given hereinafter.

It has particularly been found that compounds of formula (I) act asinhibitors of PI3-kinase, particularly as inhibitors of PI3-kinasegamma. Thus the compounds according to the invention may be used forexample for the treatment of respiratory complaints.

The present invention therefore relates to compounds of general formula(I),

wherein

-   n denotes 1, 2, 3, 4,-   A denotes CH or N,-   R¹ denotes hydrogen or a group, optionally substituted, consisting    of C₁₋₄-alkyl, OR^(1.1) and NR^(1.1)R^(1.2);-   R^(1.1), R^(1.2) which may be identical or different, denote H or    C₁₋₄-alkyl; or-   NR^(1.1)R^(1.2) denotes a 5- to 6-membered heterocycle, optionally    containing a further N atom;-   R² which may be identical or different, denote hydrogen or    -   a group selected from among F, Cl, Br, I, CN, CF₃, CF₂H, CFH₂        and NH₂; or    -   a group, optionally substituted, selected from among        —O—C₁₋₄-alkyl, C₁₋₄-alkyl and C₂₋₆-alkenyl;-   R⁴ denotes hydrogen, OH, NH₂, or    -   a group, optionally substituted, selected from among C₁₋₆-alkyl,        C₂₋₆-alkenyl, C₃₋₆-cycloalkyl, —N(C₁₋₄-alkyl)₂ and        —NH(C₁₋₄-alkyl);-   R³ a group selected from among:

wherein

-   X denotes a group, optionally substituted, selected from among    C₁₋₆-alkylene, C₂₋₆-alkenylene, C₁₋₆-alkynylene, C₃₋₇-cycloalkylene,    C₆₋₇-cycloalkenylene and —C₁₋₄-alkylene-C₃₋₇-cycloalkylene;-   Y denotes a bond or X;-   R⁵, R⁶, R⁷ which may be identical or different, denote hydrogen or a    group, optionally substituted, selected from among C₁₋₆-alkyl,    C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₁₋₆-haloalkyl, C₃₋₈-cycloalkyl,    C₃₋₈-cycloalkenyl, C₃₋₇-cycloalkyl-C₁₋₄-alkyl, aryl, heteroaryl,    spiro, heterocycloalkyl, aryl-C₁₋₆-alkyl, heteroaryl-C₁₋₆-alkyl- and    heterocycloalkyl-C₁₋₆-alkyl, or-   NR⁶R⁷ form a five-, six- or seven-membered ring consisting of carbon    atoms and optionally a nitrogen, oxygen or sulphur atom as further    heteroatoms or-   a ring selected from among:

wherein,

-   -   R^(5.1) which may be identical or different, denote hydrogen or        a group selected from among C₁₋₆-alkyl, C₃₋₈-cycloalkyl,        —CO—C₁₋₃-alkyl and CONH₂; or

-   R⁵ and R⁶ together form a saturated or unsaturated alkylene bridge    which is optionally substituted and may optionally contain a further    nitrogen, oxygen or sulphur atom;

-   or R³ is equal to

wherein

-   x, y which may be identical or different denote 0, 1, 2, 3, 4 or 5;-   W denotes O, NR⁹ or CR⁹R¹⁰;-   R⁸ denotes H, OR^(8.1), NR^(8.1)R^(8.2) or optionally substituted    C₁₋₆-alkyl;    -   R^(8.1), R^(8.2) which may be identical or different, denote        hydrogen, COR^(8.1.1), CONR^(8.1.1)R^(8.1.2),        SO₂NR^(9.1.1)R^(8.12) or SO₂R^(8.1.1)        -   or a group, optionally substituted, selected from among            C₁₋₆-alkyl, C₃₋₆-alkenyl, C₃₋₆-alkynyl, C₃₋₈-cycloalkyl and            C₃₋₇-cycloalkyl-C₁₋₄-alkyl, or    -   NR^(8.1)R^(8.2) together form a five-, six- or seven-membered        ring which may optionally contain a further heteroatom;    -   R^(8.1.1), R^(8.1.2) which may be identical or different, denote        hydrogen or a group, optionally substituted, selected from among        C₁₋₆-alkyl, C₃₋₈-cycloalkyl and C₃₋₇-cycloalkyl-C₁₋₄-alkyl, or    -   NR^(8.1.1)R^(8.1.2) together form a five- or six-membered ring,        which may optionally contain a further heteroatom;-   R⁹, R¹⁰ which may be identical or different, denote a group,    optionally substituted by OMe, CN, F, Cl or Br, selected from among    C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₈-cycloalkyl,    C₃₋₈-cycloalkenyl, C₃₋₇-cycloalkyl-C₁₋₄-alkyl, aryl, heteroaryl,    spiro, heterocycloalkyl, aryl-C₁₋₆-alkyl- and    heteroaryl-C₁₋₆-alkyl-; or-   R⁹, R¹⁰ which may be identical or different, denote hydrogen,    COR^(9.1), CONR^(9.1)R^(9.2), SO₂R^(9.1) or SO₂NR^(9.1)R^(9.2);    -   R^(9.1), R^(9.2) which may be identical or different, denote        hydrogen or an optionally substituted group selected from among        C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₁₋₆-haloalkyl,        C₃₋₈-cycloalkyl, C₃₋₇-cycloalkyl-C₁₋₄-alkyl, aryl, heteroaryl,        spiro, heterocycloalkyl, aryl-C₁₋₆-alkyl- and        heteroaryl-C₁₋₆-alkyl-; or    -   NR^(9.1)R^(9.2) together form a five- or six-membered ring,        which may optionally contain a further heteroatom,        optionally in the form of the tautomers, the racemates, the        enantiomers, the diastereomers and the mixtures thereof, and        optionally the pharmacologically acceptable acid addition salts,        solvates and hydrates thereof.

Preferred are compounds of formula (IA) according to claim 1,

wherein

-   A denotes CH, N-   R¹, R³, and R⁴ may have the meanings stated and-   R^(2a) denotes a group selected from among F, Cl, Br, I, CN, CF₃,    CF₂H, CFH₂ and NH₂; or    -   a group, optionally substituted, selected from among        —O—C₁₋₄-alkyl, C₁₋₄-alkyl and C₂₋₆-alkenyl.

Also preferred are compounds of formula (I) or (IA), wherein

-   R³ may have the meanings stated and-   n denotes 1 or 2,-   R¹ denotes C₁₋₄-alkyl or NR^(1.1)R^(1.2);-   R^(1.1), R^(1.2) which may be identical or different, denote H or    C₁₋₄-alkyl;-   R² and/or R^(2a), which may be identical or different, denote    hydrogen, F or Cl; and-   R⁴ denotes hydrogen.

Also preferred are compounds of formula (I) or (IA), wherein

-   R¹, R², R^(2a) and R⁴ may have the meanings stated and-   R³ denotes a group selected from among:

wherein

-   X denotes optionally substituted C₁₋₃-alkylene-   R⁵, R⁶, R⁷ which may be identical or different, denote hydrogen or a    group, optionally substituted, selected from among C₁₋₆-alkyl,    C₂₋₆-alkenyl, C₁₋₆-haloalkyl, C₃₋₈-cycloalkyl,    C₃₋₇-cycloalkyl-C₁₋₄-alkyl, aryl, heteroaryl, heterocycloalkyl,    aryl-C₁₋₅-alkyl, heteroaryl-C₁₋₅-alkyl, heterocycloalkyl-C₁₋₅-alkyl-    and N(C₁₋₃-alkyl)₂-C₁₋₄-alkyl, or-   NR⁶R⁷ form a five- or six-membered ring consisting of carbon atoms    and optionally a nitrogen or oxygen atom as a further heteroatom, or-   NR⁶R⁷ form a ring selected from among:

-   -   R^(5.1) which may be identical or different, denote hydrogen or        a group selected from among C₁₋₆-alkyl, C₃₋₈-cycloalkyl,        —CO—C₁₋₃-alkyl and CONH₂.

Also preferred are compounds of formula (I), wherein

-   R¹, R², and R⁴ may have the meanings stated and-   R³ denotes a group selected from among:

-   x, y which may be identical or different denote 0, 1, 2 or 3-   W denotes NR⁹ or CR⁹R¹⁰;-   R⁸ denotes H, OR^(8.1) or NR^(8.1)R^(8.2)    -   R^(8.1), R^(8.2) which may be identical or different, denote        hydrogen, COR^(8.1.1), CONR^(8.1.1)R^(8.1.2), or optionally        substituted C₁₋₆-alkyl;    -   NR^(8.1)R^(8.2) together form a five- or six-membered ring which        may optionally contain a further heteroatom;    -   R^(8.1.1), R^(8.1.2) which may be identical or different, denote        hydrogen or an optionally substituted C₁₋₆-alkyl,-   R⁹, R¹⁰ which may be identical or different, denote a group,    optionally substituted by OMe, CN, F, Cl or Br, selected from among    C₁₋₆-alkyl, C₃₋₈-cycloalkyl, C₃₋₇-cycloalkyl-C₁₋₄-alkyl or-   R⁹, R¹⁰ which may be identical or different, denote hydrogen,    COR^(9.1), CONR^(9.1)R^(9.2), SO₂R^(9.1) or SO₂NR^(9.1)R^(9.2);    -   R^(9.1), R^(9.2) which may be identical or different, denote        hydrogen or an optionally substituted group selected from among        C₁₋₆-alkyl and C₃₋₈-cycloalkyl, or    -   NR^(9.1)R^(9.2) together form a five- or six-membered ring,        which may optionally contain oxygen as a further heteroatom.

In another aspect the invention relates to compounds of formula (I) foruse as pharmaceutical compositions.

The invention further relates to the use of the compounds of formula (I)for preparing a pharmaceutical composition for the treatment of diseasesin whose pathology an activity of PI3-kinases is implicated, whereintherapeutically effective doses of the compounds of formula (I) mayconfer a therapeutic benefit.

The invention further relates to the use of the compounds of formula(I), for preparing a pharmaceutical composition for the treatment ofinflammatory and allergic diseases of the airways.

The invention further relates to the use of the compounds of formula(I), for preparing a pharmaceutical composition for the treatment of adisease, which is selected from among chronic bronchitis, bronchitiscaused by bacterial or viral infections or fungi or helminths, allergicbronchitis, toxic bronchitis, chronic obstructive bronchitis (COPD),asthma (intrinsic or allergic), paediatric asthma, bronchiectases,allergic alveolitis, allergic or non-allergic rhinitis, chronicsinusitis, cystic fibrosis or mucoviscidosis, alpha1-antitrypsindeficiency, coughing, pulmonary emphysema, interstitial lung diseases,alveolitis, hyperreactive airways, nasal polyps, pulmonary oedema,pneumonitis of various causes, such as radiation-induced or caused byaspiration or infection, collagenoses such as lupus erythematodes,systemic scleroderma, sarcoidosis and Boeck's disease.

The invention further relates to the use of the compounds of formula(I), for preparing a pharmaceutical composition for the treatment ofinflammatory and allergic diseases of the skin.

The invention further relates to the use of the compounds of formula(I), for preparing a pharmaceutical composition for the treatment of adisease which is selected from among psoriasis, contact dermatitis,atopical dermatitis, alopecia greata (circular hair loss), erythemaexsudativum multiforme (Stevens-Johnson Syndrome), dermatitisherpetiformis, sclerodermy, vitiligo, nettle rash (urticaria), lupuserythematodes, follicular and surface pyoderma, endogenous and exogenousacne, acne rosacea and other inflammatory and allergic or proliferativeskin complaints.

The invention further relates to the use of the compounds of formula(I), for preparing a pharmaceutical composition for the treatment ofinflammation of the eye.

The invention further relates to the use of the compounds of formula(I), for preparing a pharmaceutical composition for the treatment adisease which is selected from among conjunctivitis of various kinds,such as e.g. caused by fungal or bacterial infections, allergicconjunctivitis, irritable conjunctivitis, conjunctivitis caused bydrugs, keratitis and uveitis.

The invention further relates to the use of the compounds of formula(I), for preparing a pharmaceutical composition for the treatment ofdiseases of the nasal mucosa.

The invention further relates to the use of the compounds of formula(I), for preparing a pharmaceutical composition for the treatment of adisease, which is selected from among allergic rhinitis, allergicsinusitis and nasal polyps.

The invention further relates to the use of the compounds of formula(I), for preparing a pharmaceutical composition for the treatment ofinflammatory or allergic conditions involving autoimmune reactions.

The invention further relates to the use of the compounds of formula(I), for preparing a pharmaceutical composition for the treatment of adisease which is selected from among Crohn's disease, ulcerativecolitis, systemic lupus erythematodes, chronic hepatitis, multiplesclerosis, rheumatoid arthritis, psoriatric arthritis, osteoarthritis,rheumatoid spondylitis.

The invention further relates to the use of the compounds of formula(I), for preparing a pharmaceutical composition for the treatment ofkidney inflammation. The invention further relates to the use of thecompounds of formula (I), for preparing a pharmaceutical composition forthe treatment of a disease which is selected from amongglomerulonephritis, interstitial nephritis and idiopathic nephroticsyndrome.

Of particular importance according to the invention is a pharmaceuticalformulation containing a compound of formula (I).

Preferred is an orally administered pharmaceutical formulationcontaining a compound of formula (I).

The invention further relates to a process for preparing compounds ofgeneral formula (I),

whereinA, R¹ to R⁴ may have the meanings stated,characterised in that(a) a compound of formula (II)

wherein R¹ has the meaning specified,is reacted with a compound of formula

wherein R⁴ has the meaning specified and Ag denotes a leaving group, and(b) the compound of general formula (III)

resulting from step (a), wherein R¹ and R⁴ have the meanings specified,is reacted with a compound of general formula

wherein R² and n have the meanings specified and B denotes a leavinggroup, and(c) the compound of general formula (IV)

resulting from step (b), wherein R¹, R², R⁴ and n have the meaningsspecified andB denotes a leaving group,is reacted with a compound of general formula

wherein R³ has the meaning specified.

In another aspect the invention relates to compounds according togeneral formula (II),

whereinR¹ has the meanings specified,optionally in the form of the tautomers, the racemates, the enantiomers,the diastereomers and the mixtures thereof, and optionally thepharmacologically acceptable acid addition salts thereof.

In another aspect the invention relates to compounds according togeneral formula (III),

whereinR¹ and R⁴ have the meanings specified,optionally in the form of the tautomers, the racemates, the enantiomers,the diastereomers and the mixtures thereof, and optionally thepharmacologically acceptable acid addition salts thereof.

In another aspect the invention relates to compounds according togeneral formula (IV),

whereinwherein R¹, R², R⁴ and n have the meanings specified and B denotes aleaving group,optionally in the form of the tautomers, the racemates, the enantiomers,the diastereomers and the mixtures thereof, and optionally thepharmacologically acceptable acid addition salts thereof.

TERMS AND DEFINITIONS USED

Unless otherwise stated, the above-mentioned terms propyl, butyl,pentyl, hexyl, heptyl, octyl, nonyl and decyl include all the possibleisomeric forms. For example, the term propyl includes the two isomericgroups n-propyl and iso-propyl, the term butyl includes n-butyl,iso-butyl, sec. butyl and tert.-butyl, the term pentyl includesisopentyl, neopentyl etc.

In the above-mentioned alkyl groups one or more hydrogen atoms mayoptionally be substituted by other groups. For example these alkylgroups may be substituted by the halogen atoms fluorine, chlorine,bromine or iodine. The substituents fluorine and chlorine are preferred.Particularly preferred is the substituent chlorine. Optionally all thehydrogen atoms of the alkyl group may be replaced.

Unless otherwise stated, the alkyl bridge used may be a branched orunbranched alkyl group with 4 to 7 carbon atoms, for example, ann-butyl, iso-butyl, sec. butyl and tert.-butyl, pentyl, iso-pentyl,neopentyl, etc. bridge. Particularly preferred are n-butyl or n-pentylbridges. In the above-mentioned alkyl bridges 1 to 2 C atoms mayoptionally be replaced by one or more heteroatoms selected from amongoxygen or sulphur, preferably oxygen or sulphur.

By the term “C₁₋₆-alkylene” (including those which are part of othergroups) are meant branched and unbranched alkylene groups with 1 to 6carbon atoms and by the term “C₁₋₄-alkylene” are meant branched andunbranched alkylene groups with 1 to 4 carbon atoms. Preferred arealkylene groups with 1 to 4 carbon atoms. Examples include: methylene,ethylene, propylene, 1-methylethylene, butylene, 1-methylpropylene,1,1-dimethylethylene, 1,2-dimethylethylene, pentylene,1,1-dimethylpropylene, 2,2-dimethylpropylene, 1,2-dimethylpropylene,1,3-dimethylpropylene or hexylene. Unless stated otherwise, thedefinitions propyl-ene, butylene, pentylene and hexylene include all thepossible isomeric forms of the groups in question with the same numberof carbons. Thus, for example, propyl also includes 1-methylethylene andbutylene includes 1-methylpropylene, 1,1-dimethylethylene,1,2-dimethylethylene.

Examples of alkenyl groups (including those which are part of othergroups) are branched and unbranched alkylene groups with 2 to 10 carbonatoms, preferably 2-6 carbon atoms, particularly preferably 2-3 carbonatoms, provided that they have at least one double bond. Examplesinclude: ethenyl, propenyl, butenyl, pentenyl etc. Unless statedotherwise, the above-mentioned terms propenyl, butenyl etc. include allthe possible isomeric forms. For example the term butylene includesn-butenyl, 1-methylpropenyl, 2-methylpropenyl, 1,1-dimethylethenyl,1,2-dimethylethenyl etc.

In the above-mentioned alkenyl groups, unless otherwise stated,optionally one or more hydrogen atoms may optionally be replaced byother groups. For example these alkyl groups may be substituted by thehalogen atoms fluorine, chlorine, bromine or iodine. The substituentsfluorine and chlorine are preferred. Particularly preferred is thesubstituent chlorine. Optionally all the hydrogen atoms of the alkenylgroup may be replaced.

By the term “C₂₋₆-alkenylene” (including those which are part of othergroups) are meant branched and unbranched alkenylene groups with 2 to 6carbon atoms and by the term “C₂₋₄-alkenylene” are meant branched andunbranched alkylene groups with 2 to 4 carbon atoms. Alkenylene groupswith 2 to 4 carbon atoms are preferred. Examples include: ethenylene,propenylene, 1-methylethenylene, butenylene, 1-methylpropenylene,1,1-dimethylethenylene, 1,2-dimethylethenylene, pentenylene,1,1-dimethylpropenylene, 2,2-dimethylpropenylene,1,2-dimethylpropenylene, 1,3-dimethylpropenylene or hexenylene. Unlessstated otherwise, the definitions propenylene, butenylene, pentenyleneand hexenylene include all the possible isomeric forms of the groups inquestion with the same number of carbons. Thus, for example, propenylalso includes 1-methylethenylene and butenylene includes1-methylpropenylene, 1,1-dimethylethenylene, 1,2-dimethylethenylene.

Examples of alkynyl groups (including those which are part of othergroups) are branched and unbranched alkynyl groups with 2 to 10 carbonatoms, provided that they have at least one triple bond, for exampleethynyl, propargyl, butynyl, pentynyl, hexynyl etc., preferably ethynylor propynyl.

Preferred are alkynyl groups with 2 to 4 carbon atoms. Examples include:ethynyl, propynyl, butynyl, pentynyl, or hexynyl. Unless statedotherwise, the definitions propynyl, butynyl, pentynyl and hexynylinclude all the possible isomeric forms of the groups in question. Thus,for example propynyl includes 1-propynyl and 2-propynyl, butynylincludes 1-, 2- and 3-butynyl, 1-methyl-1-propynyl, 1-methyl-2-propynyletc.

In the above-mentioned alkynyl groups one or more hydrogen atoms mayoptionally be substituted by other groups unless stated otherwise. Forexample these alkyl groups may be substituted by the halogen atomsfluorine, chlorine, bromine or iodine. The substituents fluorine andchlorine are preferred. Particularly preferred is the substituentchlorine. Optionally all the hydrogen atoms of the alkynyl group may bereplaced.

By the term “C₂₋₆-alkynylene” (including those which are part of othergroups) are meant branched and unbranched alkynylene groups with 2 to 6carbon atoms and by the term “C₂₋₄-alkynylene” are meant branched andunbranched alkylene groups with 2 to 4 carbon atoms. Preferred arealkynylene groups with 2 to 4 carbon atoms. Examples include:ethynylene, propynylene, 1-methylethynylene, butynylene,1-methylpropynylene, 1,1-dimethylethynylene, 1,2-dimethylethynylene,pentynylene, 1,1-dimethylpropynylene, 2,2-dimethylpropynylene,1,2-dimethylpropynylene, 1,3-dimethylpropynylene or hexynylene. Unlessstated otherwise, the definitions propynylene, butynylene, pentynyleneand hexynylene include all the possible isomeric forms of the groups inquestion with the same number of carbons. Thus, for example propynylalso includes 1-methylethynylene and butynylene includes1-methylpropynylene, 1,1-dimethylethynylene, 1,2-dimethylethynylene.

By cycloalkyl groups (including those which are part of other groups)are meant saturated cycloalkyl groups with 3-8 carbon atoms, for examplecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl orcyclooctyl, preferably cyclopropyl, cyclopentyl or cyclohexyl, whileeach of the above-mentioned cycloalkyl groups may optionally carry oneor more substituents or be anellated to a benzene ring. Moreover thecycloalkyl groups may form, in addition to monocyclic groups, bicyclic,bridged or spirocyclic ring systems.

By cycloalkenyl (including those which are part of other groups) aremeant cyclic alkyl groups with 5 to 8, preferably 5 or 6 carbon atoms,which contain one or two double bonds. Examples include: cyclopentenyl,cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl,cycloheptadienyl, cyclooctenyl or cyclooctadienyl. Moreover thecycloalkenyl groups may form, in addition to monocyclic groups,bicyclic, bridged or spirocyclic ring systems.

By haloalkyl (including those which are part of other groups) are meantbranched and unbranched alkyl groups with 1 to 6 carbon atoms, whereinone or more hydrogen atoms are replaced by a halogen atom selected fromamong fluorine, chlorine or bromine, preferably fluorine and chlorine,particularly preferably fluorine. By the term “C₁₋₄-haloalkyl” are meantcorrespondingly branched and unbranched alkyl groups with 1 to 4 carbonatoms, wherein one or more hydrogen atoms are replaced as describedabove. C₁₋₄-haloalkyl is preferred. Examples include: CH₂F, CHF₂, CF₃.

The term aryl denotes an aromatic ring system with 6 to 14 carbon atoms,preferably 6 or 10 carbon atoms, preferably phenyl, which, unlessotherwise stated, may carry one or more substituents, for example.

By heterocycloalkyl groups are meant, unless otherwise described in thedefinitions, 5-, 6- or 7-membered, saturated or unsaturated, bridged,mono- or bicyclic heterocycles which may contain as heteroatomsnitrogen, oxygen or sulphur, for example tetrahydrofuran,tetrahydrofuranone, γ-butyrolactone, α-pyran, γ-pyran, dioxolane,tetrahydropyran, dioxane, dihydrothiophene, thiolane, dithiolane,pyrroline, pyrrolidine, pyrazoline, pyrazolidine, imidazoline,imidazolidine, tetrazole, piperidine, pyridazine, pyrimidine, pyrazine,piperazine triazine, tetrazine, morpholine, thiomorpholine, diazepan,oxazine, tetrahydro-oxazinyl, isothiazole, pyrazolidine, preferablypyrazolyl, pyrrolidinyl, piperidinyl, piperazinyl or tetrahydrooxazinyl,while the heterocycle may optionally be substituted. The ring may belinked to the molecule through a carbon atom or if available through anitrogen atom.

Unless otherwise mentioned, a heterocyclic ring may be provided with aketo group. Examples of these include.

Examples of 5-10-membered bicyclic heterorings include pyrrolizine,indole, indolizine, isoindole, indazole, purine, quinoline,isoquinoline, benzimidazole, benzofuran, benzopyran, benzothiazole,benzothiazole, benzisothiazole, pyridopyrimidine, pteridine,pyrimidopyrimidine,

Examples of heteroaryl include 5-10-membered mono- or bicyclicheteroaryl rings in which up to three C atoms may be replaced by one ormore heteroatoms selected from among oxygen, nitrogen or sulphur, whilethese may contain so many conjugated double bonds that an aromaticsystem is formed. Each of the above-mentioned heterocycles mayoptionally also be anellated to a benzene ring, preferablybenzimidazole. The heteroaryl rings may, unless otherwise described,carry one or more substituents, for example.

The ring may be linked to the molecule through a carbon atom or ifpresent through a nitrogen atom. The following are examples of five- orsix-membered heterocyclic aromatic groups:

Examples of 5-10-membered bicyclic hetaryl rings include pyrrolizine,indole, indolizine, isoindole, indazole, purine, quinoline,isoquinoline, benzimidazole, benzofuran, benzopyran, benzothiazole,benzoisothiazole, pyridopyrimidine, pteridine, pyrimidopyrimidine.

By the term heterocyclic spiro rings (“spiro”) are meant 5-10 membered,spirocyclic rings which may optionally contain one, two or threeheteroatoms, selected from among oxygen, sulphur and nitrogen, while thering may be connected to the molecule via a carbon atom or, if present,via a nitrogen atom. Unless otherwise stated, a spirocyclic ring may beprovided with a keto group. Examples include:

By the term “optionally substituted” is meant within the scope of theinvention the above-mentioned group, optionally substituted by alower-molecular group. Examples of lower-molecular groups regarded aschemically meaningful are groups consisting of 1-200 atoms. Preferablysuch groups have no negative effect on the pharmacological efficacy ofthe compounds.

For example the groups may comprise:

-   -   Straight-chain or branched carbon chains, optionally interrupted        by heteroatoms, optionally substituted by rings, heteroatoms or        other common functional groups.    -   Aromatic or non-aromatic ring systems consisting of carbon atoms        and optionally heteroatoms, which may in turn be substituted by        functional groups.    -   A number of aromatic or non-aromatic ring systems consisting of        carbon atoms and optionally heteroatoms which may be linked by        one or more carbon chains, optionally interrupted by        heteroatoms, optionally substituted by heteroatoms or other        common functional groups.

The term halogen generally denotes fluorine, chlorine, bromine oriodine.

The compounds according to the invention may occur in the form of theindividual optical isomers, mixtures of the individual enantiomers,diastereomers or racemates, in the form of the tautomers as well as inthe form of the free bases or the corresponding acid addition salts withpharmacologically acceptable acids—such as for example acid additionsalts with hydrohalic acids, for example hydrochloric or hydrobromicacid, or organic acids, such as for example oxalic, fumaric, diglycolicor methanesulphonic acid.

A may represent N or CH, preferably N.

The substituent R¹ may represent a group selected from among hydrogen ora group, optionally substituted, consisting of C₁₋₄-alkyl, OR^(1.1) andNR^(1.1)R^(1.2); preferably C₁₋₄-alkyl and NR^(1.1)R^(1.2). Particularlypreferably the substituent R¹ denotes methyl or —NH—CH₃, particularlypreferably methyl.

The substituents R^(1.1), R^(1.2) which may be identical or different,may denote H or C₁₋₄-alkyl, preferably H or methyl.

NR^(1.1)R^(1.2) may also denote a 5- to 6-membered heterocycle,optionally containing a further N atom.

The substituent R² which may be identical or different, may denotehydrogen or a group selected from among F, Cl, Br, I, CN, CF₃, CF₂H,CFH₂ and NH₂; preferably F, Cl and hydrogen, or

a group, optionally substituted, selected from among—O—C₁₋₄-alkyl, C₁₋₄-alkyl and C₂₋₆-alkenyl.

The substituent R^(2a) may represent a group selected from among F, Cl,Br, I, CN, CF₃, CF₂H, CFH₂ and NH₂, preferably hydrogen, F or Cl, or

a group, optionally substituted, selected from among —O—C₁₋₄-alkyl,C₁₋₄-alkyl and C₂₋₆-alkenyl.

The substituent R^(2b) may represent a group selected from among F, Cl,Br, I, CN, CF₃, CF₂H, CFH₂ and NH₂, preferably hydrogen, F or Cl, or

a group, optionally substituted, selected from among —O—C₁₋₄-alkyl,C₁₋₄-alkyl and C₂₋₆-alkenyl.

The substituent R³ may denote a group selected from among:

wherein

-   X denotes a group, optionally substituted, preferably unsubstituted,    selected from among C₁₋₆-alkylene, C₂₋₅-alkenylene, C₁₋₅-alkynylene,    C₃₋₇-cycloalkylene, C₅₋₇-cycloalkenylene and    —C₁₋₄-alkylene-C₃₋₇-cycloalkylene, preferably C₁₋₃-alkylene,-   Y denotes a bond or X.-   R³ may preferably represent a group selected from among

wherein

-   X denotes a group, optionally substituted, preferably unsubstituted,    selected from among C₁₋₆-alkylene, C₂₋₅-alkenylene, C₁₋₅-alkynylene,    C₃₋₇-cycloalkylene, C₅₋₇-cycloalkenylene and    —C₁₋₄-alkylene-C₃₋₇-cycloalkylene, preferably C₁₋₃-alkylene.

The substituent R³ is particularly preferably a group

whereinx, y which may be identical or different denote 0, 1, 2, 3, 4 or 5;preferably x is 0, 1 or 2, particularly preferably 2, and y is 2 or 3,preferably 2.W may represent O, NR⁹ or CR⁹R¹⁰; preferably NR⁹ or CR⁹R¹⁰.

The substituent R⁴ may represent hydrogen, OH, NH₂, or

a group, optionally substituted, selected from among C₁₋₆-alkyl,C₂₋₆-alkenyl, C₃₋₆-cycloalkyl, —N(C₁₋₄-alkyl)₂ and —NH(C₁₋₄-alkyl).

Preferably the substituent R⁴ denotes hydrogen.

The substituent R⁵ may represent hydrogen or a group, optionallysubstituted, selected from among C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl,C₁₋₆-haloalkyl, C₃₋₈-cycloalkyl, C₃₋₈-cycloalkenyl,C₃₋₇-cycloalkyl-C₁₋₄-alkyl, aryl, heteroaryl, spiro, heterocycloalkyl,aryl-C₁₋₆-alkyl, heteroaryl-C₁₋₆-alkyl- and heterocycloalkyl-C₁₋₆-alkyl,preferably C₁₋₄-alkyl and hydrogen, preferably methyl and hydrogen.

The substituent R⁶ may represent hydrogen or a group, optionallysubstituted, selected from among C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl,C₁₋₆-haloalkyl, C₃₋₈-cycloalkyl, C₃₋₈-cycloalkenyl,C₃₋₇-cycloalkyl-C₁₋₄-alkyl, aryl, heteroaryl, spiro, heterocycloalkyl,aryl-C₁₋₆-alkyl, heteroaryl-C₁₋₆-alkyl- and heterocycloalkyl-C₁₋₆-alkyl,preferably hydrogen or a group, optionally substituted, selected fromamong C₁₋₆-alkyl, C₁₋₆-haloalkyl, C₃₋₈-cycloalkyl,C₃₋₇-cycloalkyl-C₁₋₄-alkyl, aryl, heteroaryl, heterocycloalkyl- andaryl-C₁₋₆-alkyl.

The substituent R⁷ may represent hydrogen or a group, optionallysubstituted, selected from among C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl,C₁₋₆-haloalkyl, C₃₋₈-cycloalkyl, C₃₋₈-cycloalkenyl,C₃₋₇-cycloalkyl-C₁₋₄-alkyl, aryl, heteroaryl, spiro, heterocycloalkyl,aryl-C₁₋₆-alkyl, heteroaryl-C₁₋₆-alkyl- and heterocycloalkyl-C₁₋₆-alkyl,preferably hydrogen or a group, optionally substituted, selected fromamong C₁₋₆-alkyl, C₃₋₈-cycloalkyl, C₃₋₇-cycloalkyl-C₁₋₄-alkyl,heteroaryl, heteroaryl-C₁₋₆-alkyl- and heterocycloalkyl-C₁₋₆-alkyl.

NR⁶R⁷ may form a five-, six- or seven-membered ring, preferably a five-or sixmembered ring, consisting of carbon atoms and optionally anitrogen, oxygen or sulphur atom, preferably a nitrogen or oxygen atom,as further heteroatoms, orNR⁶R⁷ may form a ring selected from among:

preferably from

whereinR^(5.1) which may be identical or different, denote hydrogen or a groupselected from among C₁₋₆-alkyl, C₃₋₈-cycloalkyl, —CO—C₁₋₃-alkyl andCONH₂, preferably hydrogen or a group selected from among C₁₋₃-alkyl andC₃₋₆-cycloalkyl.

The substituent R⁸ may represent H, OR^(8.1), NR^(8.1)R^(8.2) oroptionally substituted C₁₋₆-alkyl; preferably H, OR^(8.1) orNR^(8.1)R^(8.2), particularly preferably NR^(8.1)R^(8.2), wherein

-   -   R^(8.1), R^(8.2) which may be identical or different, may        represent hydrogen, COR^(8.1.1), CONR^(8.1.1)R^(8.1.2),        SO₂NR^(8.1.1)R^(8.1.2) or SO₂R^(8.1.1), preferably hydrogen,        -   or a group, optionally substituted, selected from among            C₁₋₆-alkyl, C₃₋₆-alkenyl, C₃₋₆-alkynyl, C₃₋₈-cycloalkyl and            C₃₋₇-cycloalkyll-C₁₋₄-alkyl, preferably hydrogen,            COR^(8.1.1), CONR^(8.1.1)R^(8.1.2) or C₁₋₃₋alkyl, or    -   NR^(8.1)R^(8.2) together form a five-, six- or seven-membered        ring, preferably a five- or six-membered ring, which may        optionally contain a further heteroatom;    -   R^(8.1.1), R^(8.1.2) which may be identical or different, denote        hydrogen or a group, optionally substituted, selected from among        C₁₋₆-alkyl, C₃₋₈-cycloalkyl and C₃₋₇-cycloalkyl-C₁₋₄-alkyl,        preferably hydrogen or C₁₋₃-alkyl or    -   NR^(8.1.1)R^(8.1.2) together form a five- or six-membered ring,        which may optionally contain a further heteroatom;

The substituent R⁹ may represent a group, optionally substituted by OMe,CN, F, Cl or Br, selected from among C₁₋₆-alkyl, C₂₋₆-alkenyl,C₂₋₆-alkynyl, C₃₋₈-cycloalkyl, C₃₋₈-cycloalkenyl,C₃₋₇-cycloalkyl-C₁₋₄-alkyl, aryl, heteroaryl, spiro, heterocycloalkyl,aryl-C₁₋₆-alkyl- and heteroaryl-C₁₋₆-alkyl-; preferably C₁₋₆-alkyl,C₃₋₆-cycloalkyl and C₃₋₆-cycloalkyl-C₁₋₄-alkyl, particularly preferablyC₅₋₆-cycloalkyl or

-   -   hydrogen, COR^(9.1), CONR^(9.1)R^(9.2), SO₂R^(9.1) or        SO₂NR^(9.1)R^(9.2),        wherein    -   R^(9.1), R^(9.2) which may be identical or different, denote        hydrogen or an optionally substituted group selected from among        C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₁₋₆-haloalkyl,        C₃₋₈-cycloalkyl, C₃₋₇-cycloalkyl-C₁₋₄-alkyl, aryl, heteroaryl,        spiro, heterocycloalkyl, aryl-C₁₋₆-alkyl- and        heteroaryl-C₁₋₆-alkyl-; preferably hydrogen or an optionally        substituted group selected from among C₁₋₆-alkyl and        C₃₋₆-cycloalkyl; or    -   NR^(9.1)R^(9.2) together form a five- or six-membered ring,        which may optionally contain a further heteroatom.

The substituent R¹⁰ may represent a group, optionally substituted byOMe, CN, F, Cl or Br, selected from among C₁₋₆-alkyl, C₂₋₆-alkenyl,C₂₋₆-alkynyl, C₃₋₈-cycloalkyl, C₃₋₈-cycloalkenyl,C₃₋₇-cycloalkyl-C₁₋₄-alkyl, aryl, heteroaryl, spiro, heterocycloalkyl,aryl-C₁₋₆-alkyl- and heteroaryl-C₁₋₆-alkyl or hydrogen, COR^(9.1),CONR^(9.1)R^(9.2), SO₂R^(9.1) or SO₂NR^(9.1)R^(9.2),

wherein

-   -   R^(9.1), R^(9.2) which may be identical or different, denote        hydrogen or an optionally substituted group selected from among        C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₁₋₆-haloalkyl,        C₃₋₈-cycloalkyl, C₃₋₇-cycloalkyl-C₁₋₄-alkyl, aryl, heteroaryl,        spiro, heterocycloalkyl, aryl-C₁₋₆-alkyl- and        heteroaryl-C₁₋₆-alkyl- or    -   NR^(9.1)R^(9.2) together form a five- or six-membered ring,        which may optionally contain a further heteroatom

Particularly preferably the group R¹⁰ denotes hydrogen.

The leaving group A is a leaving group such as for example chlorine,O—C₁-C₃-alkyl, imidazolidine, preferably O—C₁-C₃-alkyl.

The leaving group B is a leaving group such as for example chlorine,bromine, iodine, methanesulphonyl, trifluoromethanesulphonyl orp-toluenesulphonyl, preferably iodine.

Preparation Processes

The compounds of general formula (I) may be prepared according to thefollowing synthesis plan (Diagram 1), wherein the substituents ofgeneral formula (I) have the meanings given above. These processes areto be understood as illustrating the invention without restricting it totheir content.

The new compounds of general formula (I) may be prepared analogously tothe following Examples. The Examples described below are intended toillustrate the invention without restricting it.

Synthesis of the Reagents 1-cyclopentyl-4-ethynyl-piperidine

5.0 g (43.4 mmol) piperidin-4-yl-methanol are placed in 250 mLdichloromethane under an argon atmosphere and combined with 3.7 g (44.0mmol) cyclopentanone. Then 3.6 g (44.0 mmol) sodium acetate and 14.0 g(66.0 mmol) sodium triacetoxyborohydride are added. The resultingsuspension is stirred for 16 hours at ambient temperature. Then thereaction mixture is extracted with sodium hydrogen carbonate solution.The aqueous phase is saturated with sodium chloride and extracted withchloroform/methanol. The resulting organic phase is dried and evaporatedto dryness. Yield: 6.0 g

1.1 mL (13.0 mmol) oxalyl chloride are placed in 200 mL dichloromethaneunder a nitrogen atmosphere and cooled to −78° C. 1.9 mL (27.3 mmol)dimethylsulphoxide dissolved in a little dichloromethane are addeddropwise. The mixture is stirred for 0.3 hours, and then 2.0 g (10.9mmol) of the intermediate described above in dichloromethane is addeddropwise. The reaction mixture is stirred for 3 hours, then 7.9 mL (54.6mmol) triethylamine are added dropwise. The cooling is removed and thereaction mixture is heated to ambient temperature. Then water is addedand the phases are separated. The organic phase is washed with sodiumhydrogen carbonate solution (50%) and water, dried and evaporated todryness. Yield: 1.1 g

1.1 g (6.0 mmol) of the intermediate described above are dissolved in 50mL methanol under an argon atmosphere and combined with 0.8 g (6.0 mmol)potassium carbonate. 1.2 g (6.2 mmol) dimethyl(1-diazo-2-oxo-propyl)-phosphate are dissolved in methanol and added tothe mixture, then stirred for 4 hours at ambient temperature. Then thereaction mixture is poured onto 200 mL water and extracted with diethylether. The organic phase is dried and evaporated to dryness.

Yield: 0.9 g

4-Ethynyl-1-isopropyl-piperidine and1-cyclopentyl-methyl-4-ethynyl-piperidine are prepared analogously.

tert.butyl 4-ethynyl-piperidine-1-carboxylate

Can be prepared analogously to 1-cyclopentyl-4-ethynyl-piperidinestarting from commercial 1-Boc-4-piperidinemethanol.

1-cyclopentyl-4-ethynyl-piperidin-4-ol

4.0 g (28.0 mmol) piperidone-4-ethyleneacetal are placed in 250 mLdichloromethane and combined with 2.4 g (28.5 mmol) cyclopentanone. Then2.3 g (28.0 mmol) sodium acetate and 8.9 g (42 mmol) sodiumtriacetoxyborohydride are added. The resulting suspension is stirred for16 hours at ambient temperature. Then the reaction mixture is extractedwith sodium hydrogen carbonate solution and washed with water. Theorganic phase is dried and evaporated to dryness.

Yield: 5.5 g

5.5 g (26.0 mmol) of the intermediate described above are placed in 10mL acetone and combined with 110 mL 0.1 N aqueous hydrochloric acid. Thereaction mixture is refluxed for 5 hours with stirring, then aftercooling to ambient temperature made basic with 5 N sodium hydroxidesolution and extracted with chloroform/dichloromethane. The organicphase is dried and evaporated to dryness. Yield: 4.1 g

3.1 mL (18.0 mmol) trimethylsilylacetylene are placed in 400 mL drytetrahydrofuran under a nitrogen atmosphere at −70° C. and combined with12.9 mL (22.4 mmol) n-butyllithium (2.5 M solution in hexane). After onehour 3.0 g (18.0 mmol) of the intermediate described above are dissolvedin 100 mL tetrahydrofuran and slowly added dropwise to the mixture. Thisis stirred for 1 hour at −70° C. and for 16 hours at ambienttemperature. Then the reaction mixture is combined with 300 mL saturatedammonium chloride solution, stirred for 0.1 hour, then poured onto 500mL water. It is extracted with ethyl acetate, the combined organicphases are washed with water, dried and evaporated to dryness.

Yield: 3:0 g

3.0 g (11.0 mmol) of the intermediate described above and 4.1 mL (14.0mmol) tetrabutylammonium fluoride are stirred in dichloromethane for 1hour at ambient temperature. Then the reaction mixture is washed withwater, the organic phase is dried and evaporated to dryness. Yield: 0.9g

4-Ethynyl-1-isopropyl-piperidin-4-ol may be prepared analogously.

(R)-2-ethynyl-pyrrolidine

A mixture of 4.9 g (24.6 mmol) (R)-(+)-1-Boc-2-pyrrolidinecarbaldehydeand 4.0 g (29.0 mmol) potassium carbonate in 40 mL methanol is combinedwith 5.3 g (27.3 mmol) dimethyl (1-diazo-2-oxo-propyl)-phosphate andstirred for 4 hours at ambient temperature. Then the reaction mixture ispoured onto water and extracted with diethyl ether. The organic phase isdried and gently evaporated down. The residue is combined with 3 mLethereal hydrochloric acid (1 M), stirred overnight at ambienttemperature and then evaporated down completely. Yield: 3.9 g (yellowoil)

(S)-2-ethynyl-pyrrolidine may be prepared analogously starting from(S)-(−)-1-Boc-2-pyrrolidinecarbaldehyde.

1-ethynyl-1-methoxy-cyclohexane

At ambient temperature 0.8 g (20 mmol) sodium hydride (60% in mineraloil) are added to a solution of 2 g (16 mmol) 1-ethynylcyclohexanol in25 mL DMF. After 20 minutes 1.25 mL (20 mmol) methyliodide are added andstirring is continued for another hour. The reaction mixture is combinedwith ice and extracted with ether. The organic phase is dried andevaporated down. The residue remaining is purified by MPLC(dichloromethane/methanol 100:5). Yield: 0.6 g (clear oil)

4-Ethynyl-4-methoxy-1-methyl-piperidine and1-cyclopentyl-4-ethynyl-4-methoxypiperidine may be prepared analogously.

Ethyl-(1-ethynyl-cyclohexyl)-amine

A solution consisting of 20 g (161 mmol) ethynylcyclohexanol and 25 mL(177 mmol) triethylamine and 200 mg (1.6 mmol) 4-dimethylaminopyridinein 200 mL dichloromethane is combined at 0° C. with 12.6 mL (177 mmol)acetyl chloride. After 5 hours at 0° C. the reaction mixture is combinedwith water and extracted with dichloromethane. The combined organicphases are evaporated down and the residue is purified by MPLC(cyclohexane/ethyl acetate 6:1). Yield: 3 g (yellow oil)

A mixture of 0.4 g (2.4 mmol) of the intermediate described above, 3.6mL (7.2 mmol) ethylamine (2 M solution in THF) and 12 mg (0.12 mmol)copper(I)-chloride in 5 mL THF is refluxed for 3.5 hours. The reactionmixture is evaporated down, taken up in ethyl acetate and washed withammonium chloride and sodium chloride solution. The organic phase isevaporated down. Yield: 0.15 g (brown oil)

The following amines may be prepared analogously:1-(1-ethynyl-cyclohexyl)-pyrrolidine;(1-ethynyl-cyclohexyl)-dimethylamine;(1-ethynyl-cyclohexyl)-isopropylamine;1-ethynyl-cyclohexyl)-methylamine; (1-ethynyl-cyclopentyl)-dimethylamine

N-(1-ethynyl-cyclohexyl)-acetamide

A solution of 4 g (32 mmol) 1-ethynylcyclohexylamine in 30 mL ether iscombined at ambient temperature with 1.1 mL (15 mmol) acetyl chloride.The colourless suspension is stirred overnight at ambient temperature,the resulting solid is suction filtered and washed with diethylether/dichloromethane. The filtrate is evaporated down and yields theproduct as a colourless solid. Yield: 3 g

N-but-3-ynyl-N-methyl-acetamide may be prepared analogously frombut-3-ynyl-methyl-amine.

1-(1-ethynyl-cyclohexyl)-3-methylurea

A solution of 1 g (8 mmol) 1-ethynylcyclohexylamine and 2 mL (15 mmol)triethylamine in 10 mL acetonitrile is combined at ambient temperaturewith 0.5 g (9 mmol) methylisocyanate. The colourless suspension isstirred overnight at ambient temperature and then evaporated down. Theresidue is taken up in dichloromethane and washed with aqueous potassiumcarbonate solution. The organic phase is dried and evaporated down.Yield: 1.4 g (colourless solid)

1-But-3-ynyl-1,3-dimethyl-urea may be prepared analogously frombut-3-ynyl-methyl-amine.

1-prop-2-ynyl-1H-imidazole

5 g (73 mmol) imidazole and 1.3 g (4 mmol) tetrabutylammonium iodide areplaced in 200 mL toluene and 150 mL 50% sodium hydroxide solution and15.7 mL (145 mmol) propargyl bromide are added. The mixture is stirredfor 1 hour at ambient temperature, then diluted with toluene and water.The organic phase is dried and evaporated to dryness. The residue ispurified by chromatography. Yield: 2.5 g

2-chloro-5-iodo-benzamidine

374.8 mL (374.8 mmol) lithium bis-trimethylsilylamide (1 M in hexane)are placed in 300 mL diethyl ether and combined with 50.0 g (189.8 mmol)2-chloro-5-iodobenzonitrile. The reaction mixture is stirred for 1.5hours at ambient temperature under an argon atmosphere and then cooledto 0° C. Then 5 molar hydrochloric acid is slowly added. The precipitatethus formed is suction filtered and dried.

Yield: 56.0 g

3-Chloro-5-iodo-benzamidine, 2-fluoro-5-iodo-benzamidine as well as3-iodo-benzamidine may be prepared analogously.

Synthesis of the Intermediate CompoundsN-(7-oxo-4,5,6,7-tetrahydro-benzothiazol-2-yl)-acetamide

112 g (1.0 mol) 1,3-cyclohexanedione are suspended in 700 mL ice waterand 51.6 mL (1.0 mol) bromine are added dropwise at 0° C. within 45minutes. The suspension is stirred for 3.5 hours at max. 10° C. Then itis suction filtered and the solid is stirred in 800 mL water, suctionfiltered, washed with 3 L water and dried. The solid obtained isrecrystallised from ethanol. Yield: 37 g (m.p.: 159-160° C.) 15.5 g (0.2mol) thiourea are placed in 200 mL ethanol at ambient temperature. 37.1g (0.2 mol) of the intermediate described above are added batchwise tothis suspension, then it is rinsed with 60 mL ethanol. The solution thatgradually forms is refluxed for 2 hours with stirring and thenevaporated down. The residue is extracted with water and diethyl ether,the aqueous phase is made basic with sodium carbonate solution. Theresulting solid is suction filtered, washed with water, then extractedwith methanol and evaporated to dryness.

Yield: 22 g (m.p.: 265-268° C.)

230 mL (2.4 mol) acetic anhydride are placed at ambient temperature, 22g (0.13 mol) of the intermediate described above are added and themixture is refluxed for 3 hours with stirring. The suspension goespartly into solution. After cooling with ice/saline bath the solid issuction filtered, decocted 2× in 150 mL acetone, suction filtered anddried.

Yield: 25 g (m.p.: 268-272° C.)

N-(6-formyl-7-oxo-4,5,6,7-tetrahydro-benzothiazol-2-yl)-acetamide

20 g (0.37 mol) sodium methoxide are suspended in 50 mLdimethylformamide, a suspension of 21 g (0.1 mol)N-(7-oxo-4,5,6,7-tetrahydro-benzothiazol-2-yl)-acetamide in 100 mLdimethylformamide is added dropwise. The mixture is stirred for 15minutes, then cooled to 0° C. A mixture of 29.9 mL (0.37 mol) ethylformate and 60 mL benzene is added dropwise and the reaction mixture isdiluted with another 100 mL benzene. A precipitate gradually settles outand stirring is continued at 0° C. for 3.5 hours. The suspension ishydrolysed with 370 mL 1 molar hydrochloric acid, the solid precipitatedis suction filtered. The two phases of the mother liquor are separated,the aqueous phase is extracted with dichloromethane. The resultingorganic phase is dried and evaporated to dryness. The solid and theresidue from the extraction are recrystallised from acetonitrile. Yield:20 g

N-[8-(2-chloro-5-iodo-phenyl)-4,5-dihydrothiazolo[4,5-h]quinazolin-2-yl]-acetamide

5.0 g (21.0 mmol)N-(6-formyl-7-oxo-4,5,6,7-tetrahydro-benzothiazol-2-yl)-acetamide and7.3 g (23.0 mmol) 2-chloro-5-iodo-benzamidine are stirred in 50 mLpyridine for several hours at 160° C. After cooling to ambienttemperature the precipitated solid is suction filtered, washed anddried. Yield: 4.7 g

The following intermediates may be prepared analogously starting from3-chloro-5-iodo-benzamidine, 2-fluoro-5-iodo-benzamidine and3-iodo-benzamidine:N-[8-(3-chloro-5-iodo-phenyl)-4,5-dihydro-thiazolo[4,5-h]quinazolin-2-yl]-acetamide;N-[8-(2-fluoro-5-iodo-phenyl)-4,5-dihydro-thiazolo[4,5-h]quinazolin-2-yl]-acetamide;N-[8-(3-iodo-phenyl)-4,5-dihydro-thiazolo[4,5-h]quinazolin-2-yl]-acetamide

Synthesis of Compounds of Formula (I)

The following HPLC-MS methods were used to characterise the compounds offormula (I):

HPLC-MS Analysis Method A

Waters ZMD, Alliance 2690/2695 HPLC, Waters 2700 Autosampler, Waters996/2996 diode array detector

The following mobile phase was used:

A: water with 0.10% TFAB: acetonitrile with 0.10% TFA

time in min % A % B flow rate in ml/min 0.0 95 5 1.00 0.1 95 5 1.00 3.12 98 1.00 4.5 2 98 1.00 5.0 95 5 1.00

The stationary phase used was an XTerra® column, MS C₁₈ 2.5 μm, 4.6mm×30 mm (column temperature: constant at 25° C.).

The diode array detection was carried out in the wavelength range210-400 nm.

Method B

Waters ZMD, Alliance 2690/2695 HPLC, Waters 2700 Autosampler, Waters996/2996 diode array detector

The following mobile phase was used:

A: water with 0.10% TFAB: acetonitrile with 0.10% TFA

time in min % A % B flow rate in ml/min 0.00 95 5 2.00 0.10 95 5 2.002.10 2 98 2.00 3.00 2 98 2.00 3.25 95 5 2.00

The stationary phase used was a Merck Chromolith™ column SpeedRODRP-18e, 4.6 mm×50 mm (column temperature: constant at 25° C.).

The diode array detection was carried out in the wavelength range210-400 nm.

EXAMPLES Example 1N-{8-[2-chloro-5-(3-methylamino-prop-1-ynyl)-phenyl]-4,5-dihydro-thiazolo[4,5-h]quinazolin-2-yl}-acetamide

1.0 g (2.1 mmol)N-[8-(2-chloro-5-iod-phenyl)-4,5-dihydro-thiazolo[4,5-h]quinazolin-2-yl]-acetamideare placed in 50 mL tetrahydrofuran under an argon atmosphere andcombined with 0.6 ml (9 mmol) N-methylpropargylamine and 1 mL (6 mmol)diisopropylethylamine. The mixture is kept free from oxygen and 29 mg(0.04 mmol) triphenylphosphine palladium(II)-chloride and 8 mg (0.04mmol) copper(I)-iodide are added. The mixture is stirred for 5 hours at80° C. After cooling to ambient temperature the reaction mixture iscombined with water and 10% ammonia solution and extracted withdichloromethane. The organic phase is dried and evaporated to dryness.The residue is purified by chromatography, the product obtained istriturated with diethyl ether and suction filtered.

Yield: 0.27 g (MH+=424; RT=2.31; Method A)

The following compounds may be prepared analogously:

TABLE 1

Ex- analysis ample R¹ R^(2a) R^(2b) R⁴ R³ HPLC-MS 1 H₃C—X₁

H H

MH+ = 424 RT = 2.31 Method A 2

H H

3 H₃C—X₁

H H

MH+ = 516 RT = 2.51 Method A 4

H H

MH+ = 563 RT = 2.36 Method A 5 H₃C—X₁

H H

MH+ = 532 RT = 2.42 Method A 6

H H

7 H₃C—X₁

H H

MH+ = 546 RT = 2.58 Method A 8 H₃C—X₁

H H

MH+ = 548 RT = 2.48 Method A 9 H₃C—X₁

H H

MH+ = 532 RT = 2.58 Method A 10 H₃C—X₁

H H

MH+ = 562 RT = 2.64 Method A 11 H₃C—X₁ H H H

MH+ = 514 RT = 2.50 Method A 12 H₃C—X₁

H H

MH+ = 492 RT = 2.41 Method A 13 H₃C—X₁

H H

MH+ = 508 RT = 2.50 Method A 14 H₃C—X₁

H H

MH+ = 522 RT = 2.34 Method A 15 H₃C—X₁

H H

MH+ = 450 RT = 1.63 Method B 16 H₃C—X₁ H H H

MH+ = 498 RT = 2.26 Method A 17 H₃C—X₁

H H

MH+ = 506 RT = 2.27 Method A 18 H₃C—X₁

H H

MH+ = 506 RT = 2.55 Method A 19 H₃C—X₁

H H

MH+ = 546 RT = 2.72 Method A 20 H₃C—X₁

H H

MH+ = 494 RT = 2.31 Method A 21 H₃C—X₁

H H

MH+ = 492 RT = 2.52 Method A 22 H₃C—X₁

H H

MH+ = 478 RT = 2.52 Method A 23 H₃C—X₁

H H

MH+ = 450 RT = 1.62 Method B 24 H₃C—X₁

H H

MH+ = 520 RT = 2.44 Method A 25 H₃C—X₁

H H

MH+ = 466 RT = 2.34 Method A 26 H₃C—X₁

H H

MH+ = 492 RT = 1.77 Method B 27 H₃C—X₁ H H H

MH+ = 444 RT = 2.48 Method A 28 H₃C—X₁

H H

29 H₃C—X₁

H H

MH+ = 438 RT = 2.33 Method A 30 H₃C—X₁ H H H

MH+ = 488 RT = 2.34 Method A 31 H₃C—X₁

H H

MH+ = 536 RT = 2.81 Method A 32 H₃C—X₁

H H

MH+ = 506 RT = 2.56 Method A 33 H₃C—X₁

H H

MH+ = 520 RT = 3.03 Method A 34 H₃C—X₁

H H

MH+ = 532 RT = 2.63 Method A 35 H₃C—X₁

H H

MH+ = 535 RT = 2.98 Method A 36 H₃C—X₁ H H H

MH+ = 512 RT = 2.75 Method A 37 H₃C—X₁

H H

MH+ = 461 RT = 2.39 Method A 38 H₃C—X₁ H H H

MH+ = 460 RT = 2.30 Method A 39 H₃C—X₁ H H H

MH+ = 472 RT = 2.55 Method A 40 H₃C—X₁

H H

MH+ = 466 RT = 2.44 Method A 41 H₃C—X₁

H H

MH+ = 452 RT = 2.44 Method A 42 H₃C—X₁

H H

MH+ = 520 RT = 2.61 Method A 43 H₃C—X₁

H H

MH+ = 466 RT = 2.46 Method A 44 H₃C—X₁

H H

MH+ = 479 RT = 3.09 Method A 45 H₃C—X₁

H H

MH+ = 506 RT = 2.62 Method A 46 H₃C—X₁

H H

MH+ = 425 RT = 2.65 Method A 47 H₃C—X₁ H H H

MH+ = 404 RT = 2.35 Method A 48 H₃C—X₁ H H H

MH+ = 390 RT = 2.30 Method A 49 H₃C—X₁

H H

MH+ = 461 RT = 2.38 Method A 50 H₃C—X₁

H H

MH+ = 463 RT = 3.90 Method A 51 H₃C—X₁

H H

MH+ = 477 RT = 3.63 Method A 52 H₃C—X₁

H H

MH+ = 493 RT = 3.73 Method A 53 H₃C—X₁ H

H

MH+ = 478 RT = 2.84 Method A 54 H₃C—X₁ H

H

MH+ = 438 RT = 2.60 Method A 55 H₃C—X₁ H

H

MH+ = 432 RT = 2.97 Method A 56 H₃C—X₁

H H

MH+ = 462 RT = 3.95 Method A 57 H₃C—X₁

H H

MH+ = 424 RT = 3.06 Method A 58 H₃C—X₁

H H

MH+ = 507 RT = 2.24 Method B 59 H₃C—X₁

H H

MH+ = 458 RT = 1.79 Method B 60 H₃C—X₁

H H

MH+ = 457 RT = 2.39 Method B 61 H₃C—X₁

H H

MH+ = 458 RT = 1.78 Method B 62 H₃C—X₁

H H

MH+ = 493 RT = 2.50 Method A 63 H₃C—X₁

H H

MH+ = 478 RT = 2.42 Method A 64 H₃C—X₁

H H

MH+ = 466 RT = 2.43 Method A 65 H₃C—X₁

H H

MH+ = 506 RT = 2.66 Method A 66 H₃C—X₁

H H

MH+ = 495 RT = 2.39 Method A 67 H₃C—X₁

H H

MH+ = 507 RT = 2.23 Method A 68 H₃C—X₁

H H

MH+ = 480 RT = 2.38 Method A 69 H₃C—X₁

H H

MH+ = 535 RT = 2.26 Method A 70 H₃C—X₁

H H

MH+ = 495 RT = 1.80 Method B 71 H₃C—X₁

H H

MH+ = 480 RT = 1.84 Method B

Example 72N-(8-{5-[3-(acetyl-methyl-amino)-prop-1-ynyl]-2-chloro-phenyl}-4,5-dihydro-thiazolo[4,5-h]quinazolin-2-yl)-acetamide

25 μl acetic acid and 80 mg (0.25 mmol)O-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate(TBTU) are placed in 5 mL dichloromethane, combined with 65 μLdiisopropylethylamine and stirred for 0.5 hours at ambient temperature.65 mg (0.15 mmol)N-{8-[2-chloro-5-(3-methylamino-prop-1-ynyl)-phenyl]-4,5-dihydro-thiazolo[4,5-h]quinazolin-2-yl}-acetamideare added, then the mixture is stirred for 16 hours at ambienttemperature. Then the reaction mixture is extracted with potassiumcarbonate solution and dichloromethane. The organic phase is dried andevaporated to dryness. The residue is purified by chromatography.

Yield: 12 mg (MH+=466; RT=2.70; Method A)

The following compounds may be prepared analogously, starting fromN-{8-[2-chloro-5-(3-methylamino-prop-1-ynyl)-phenyl]-4,5-dihydro-thiazolo[4,5-h]quinazolin-2-yl}-acetamide(Example 1) orN-{8-[5-(3-amino-prop-1-ynyl)-2-chloro-phenyl]-4,5-dihydro-thiazolo[4,5-h]quinazolin-2-yl}-acetamide(Example 28)

TABLE 2

analysis Example R¹ R^(2a) R^(2b) R⁴ R³ HPLC-MS 72 H₃C—X₁

H H

MH+ = 466 RT = 2.70 Method A 73 H₃C—X₁

H H

MH+ = 508 RT = 3.01 Method A 74 H₃C—X₁ H H H

MH+ = 472 RT = 2.99 Method A 75 H₃C—X₁

H H

MH+ = 494 RT = 2.96 Method A 76 H₃C—X₁ H H H

MH+ = 474 RT = 3.10 Method A 77 H₃C—X₁

H H

MH+ = 518 RT = 2.31 Method A 78 H₃C—X₁

H H

MH+ = 502 RT = 3.05 Method A 79 H₃C—X₁

H H

MH+ = 494 RT = 2.88 Method A 80 H₃C—X₁

H H

MH+ = 520 RT = 3.17 Method A 81 H₃C—X₁

H H

MH+ = 506 RT = 2.97 Method A 82 H₃C—X₁

H H

MH+ = 520 RT = 3.08 Method A 83 H₃C—X₁

H H

MH+ = 478 RT = 2.80 Method A 84 H₃C—X₁

H H

MH+ = 495 RT = 2.29 Method A 85 H₃C—X₁

H H

MH+ = 534 RT = 3.17 Method A 86 H₃C—X₁

H H

MH+ = 492 RT = 2.79 Method A 87 H₃C—X₁

H H

MH+ = 508 RT = 3.04 Method A 88 H₃C—X₁ H

H

MH+ = 508 RT = 3.57 Method A 89 H₃C—X₁ H H H

MH+ = 418 RT = 2.60 Method A 90 H₃C—X₁

H H

MH+ = 480 RT = 2.82 Method A 91 H₃C—X₁

H H

MH+ = 452 RT = 2.58 Method A 92 H₃C—X₁ H H H

MH+ = 501 RT = 2.36 Method A 93 H₃C—X₁

H H

MH+ = 549 RT = 2.32 Method A 94 H₃C—X₁

H H

MH+ = 534 RT = 3.21 Method A

Example 95N-(8-{2-chloro-5-[3-(methanesulphonyl-methyl-amino)-prop-1-ynyl]-phenyl}-4,5-dihydro-thiazolo[4,5-h]quinazolin-2-yl)-acetamide

A mixture of 65 mg (0.15 mmol)N-{8-[2-chloro-5-(3-methylamino-prop-1-ynyl)-phenyl]-4,5-dihydro-thiazolo[4,5-h]quinazolin-2-yl}-acetamide,100 μL triethylamine and 30 μL methanesulphonic acid chloride in 1 mLdichloromethane is stirred overnight at ambient temperature. Thereaction mixture is washed with saturated aqueous sodium hydrogencarbonate solution and the organic phase is evaporated down. The residueremaining is stirred with ether. Yield: 55 mg yellow solid (MH+=502;RT=2.98; Method A)

The following compounds may be prepared analogously, starting fromN-{8-[2-chloro-5-(3-methylamino-prop-1-ynyl)-phenyl]-4,5-dihydro-thiazolo[4,5-h]quinazolin-2-yl}-acetamide(Example 1) orN-{8-[5-(3-amino-prop-1-ynyl)-2-chloro-phenyl]-4,5-dihydro-thiazolo[4,5-h]quinazolin-2-yl}-acetamide(Example 28).

TABLE 3

analysis Example R¹ R^(2a) R^(2b) R⁴ R³ HPLC-MS  95 H₃C—X₁

H H

MH+ = 486 RT = 2.90 Method A  96 H₃C—X₁

H H

MH+ = 502 RT = 3.07 Method A  97 H₃C—X₁

H H

MH+ = 528 RT = 3.18 Method A  98 H₃C—X₁

H H

MH+ = 514 RT = 2.86 Method A  99 H₃C—X₁

H H

MH+ = 530 RT = 3.18 Method A 100 H₃C—X₁

H H

MH+ = 531 RT = 3.15 Method A 101 H₃C—X₁

H H

MH+ = 516 RT = 2.88 Method A 102 H₃C—X₁

H H

MH+ = 517 RT = 2.91 Method A 103 H₃C—X₁

H H

MH+ = 489 RT = 1.74 Method B 104 H₃C—X₁

H H

MH+ = 556 RT = 2.86 Method A 105 H₃C—X₁

H H

MH+ = 488 RT = 2.73 Method A 106 H₃C—X₁

H H

MH+ = 530 RT = 1.99 Method B 107 H₃C—X₁

H H

MH+ = 557 RT = 3.25 Method A 108 H₃C—X₁

H H

MH+ = 516 RT = 3.08 Method A 109 H₃C—X₁ H

H

MH+ = 502 RT = 3.47 Method A 110 H₃C—X₁

H H

MH+ = 540 RT = 1.96 Method B 111 H₃C—X₁

H H

MH+ = 570 RT = 3.25 Method A 112 H₃C—X₁ H H H

MH+ = 483 RT = 2.98 Method A 113 H₃C—X₁

H H

MH+ = 545 RT = 3.15 Method A 114 H₃C—X₁

H H

MH+ = 558 RT = 1.88 Method B 115 H₃C—X₁

H H

MH+ = 543 RT = 3.02 Method A 116 H₃C—X₁

H H

MH+ = 550 RT = 2.03 Method B 117 H₃C—X₁ H H H

MH+ = 480 RT = 2.95 Method A 118 H₃C—X₁ H

H

MH+ = 488 RT = 3.21 Method A 119 H₃C—X₁

H H

MH+ = 564 RT = 2.05 Method B 120 H₃C—X₁

H H

MH+ = 556 RT = 3.20 Method A 121 H₃C—X₁

H H

MH+ = 573 RT = 2.01 Method B 122 H₃C—X₁

H H

MH+ = 542 RT = 2.10 Method B 123 H₃C—X₁

H H

MH+ = 587 RT = 1.96 Method B

Example 124N-(8-{2-chloro-5-[3-(3-methyl-ureido)-prop-1-ynyl]-phenyl}-4,5-dihydro-thiazolo[4,5-h]quinazolin-2-yl)-acetamide

A mixture of 150 mg (0.37 mmol)N-{8-[5-(3-amino-prop-1-ynyl)-2-chloro-phenyl]-4,5-dihydro-thiazolo[4,5-h]quinazolin-2-yl}-acetamide,0.1 mL (0.68 mmol) triethylamine and 40 mg (0.70 mmol) methylisocyanatein 4 mL acetonitrile is stirred overnight at ambient temperature. Theprecipitated solid is suction filtered and washed with ether.

Yield: 133 mg yellow solid (mp.: 133° C.).

The following compounds may be prepared analogously, starting fromN-{8-[2-chloro-5-(3-methylamino-prop-1-ynyl)-phenyl]-4,5-dihydro-thiazolo[4,5-h]quinazolin-2-yl}-acetamide(Example 1).

TABLE 4

HPLC-MS Example R¹ R^(2a) R^(2b) R⁴ R³ analysis 124 H₃C—X₁

H H

MH+ = 467 RT = 2.53 Method A 125 H₃C—X₁

H H

MH+ = 481 RT = 2.60 Method A 126 H₃C—X₁

H H

MH+ = 495 RT = 2.73 Method A 127 H₃C—X₁

H H

MH+ = 509 RT = 2.96 Method A 128 H₃C—X₁

H H

MH+ = 481 RT = 2.62 Method A 129 H₃C—X₁

H H

MH+ = 521 RT = 2.89 Method A 130 H₃C—X₁

H H

MH+ = 507 RT = 2.74 Method A 131 H₃C—X₁

H H

MH+ = 549 RT = 3.16 Method A

Example 132N-{8-[2-chloro-5-(3-cyclopentylamino-prop-1-ynyl)-phenyl]-4,5-dihydro-thiazolo[4,5-h]quinazolin-2-yl}-acetamide

Under a protective gas atmosphere 2.0 g (4.1 mmol)N-[8-(2-chloro-5-iodo-phenyl)-4,5-dihydro-thiazolo[4,5-h]quinazolin-2-yl]-acetamideand 0.7 mL diisopropylethylamine are dissolved in 50 mL THF and combinedwith 0.7 ml (11.6 mmol) propargylalcohol, 290 mg (0.4 mmol)triphenylphosphine palladium (II)-chloride and 79 mg (0.4 mmol)copper(I)-iodide. The reaction mixture is heated to 80° C. for 1.5 hoursand then evaporated down. The residue is stirred with dichloromethaneand the solid obtained is suction filtered.

Yield: 1.7 g yellow solid.

200 mg (0.49 mmol) of the intermediate described above and 0.1 mLtriethylamine are suspended in 20 mL dichloromethane and at 0° C.combined with 50 μL methanesulphonic acid chloride. After three hoursthe reaction mixture is combined with another 0.2 mL methanesulphonicacid chloride and a spatula tip of 4-dimethylaminopyridine and stirredfor 30 minutes at ambient temperature. The mixture is concentrated byrotary evaporation and used directly in the next reaction. Yield: 120 mgviscous yellow oil.

60 mg (0.12 mmol) of the methanesulphonate intermediate described aboveare dissolved in 1 mL dimethylformamide and combined with 13 mg (0.15mmol) cyclopentylamine. The reaction mixture is stirred overnight at 50°C. Then another 150 mg cyclopentylamine are added and the mixture isstirred for two hours at 70° C. The mixture is purified by RP-HPLC.Yield: 22 mg of light yellow solid.

The following compounds may be prepared analogously, starting fromN-{8-[2-chloro-5-(3-methylamino-prop-1-ynyl)-phenyl]-4,5-dihydro-thiazolo[4,5-h]quinazolin-2-yl}-acetamide(Example 1).

TABLE 5

HPLC-MS Example R¹ R^(2a) R^(2b) R⁴ R³ analysis 132 H₃C—X₁

H H

MH+ = 478 RT = 2.46 Method A 133 H₃C—X₁

H H

MH+ = 493 RT = 2.57 Method A 134 H₃C—X₁

H H

135 H₃C—X₁

H H

MH+ = 452 RT = 2.40 Method A 136 H₃C—X₁

H H

MH+ = 467 RT = 2.44 Method A 137 H₃C—X₁

H H

MH+ = 547 RT = 2.46 Method A 138 H₃C—X₁

H H

MH+ = 438 RT = 2.30 Method A 139 H₃C—X₁

H H

MH+ = 528 RT = 2.54 Method A 140 H₃C—X₁

H H

MH+ = 507 RT = 2.19 Method A 141 H₃C—X₁

H H

MH+ = 507 RT = 2.28 Method A 142 H₃C—X₁

H H

MH+ = 521 RT = 2.35 Method A 143 H₃C—X₁

H H

144 H₃C—X₁

H H

145 H₃C—X₁

H H

MH+ = 466 RT = 2.38 Method A 146 H₃C—X₁

H H

MH+ = 507 RT = 1.79 Method A 147 H₃C—X₁

H H

148 H₃C—X₁

H H

MH+ = 501 RT = 1.65 Method B 149 H₃C—X₁

H H

MH+ = 515 RT = 1.72 Method B 150 H₃C—X₁

H H

MH+ = 493 RT = 2.28 Method A 151 H₃C—X₁

H H

MH+ = 480 RT = 2.54 Method A 152 H₃C—X₁

H H

153 H₃C—X₁

H H

MH+ = 480 RT = 1.71 Method B 154 H₃C—X₁

H H

MH+ = 464 RT = 1.68 Method B

Example 155N-[8-(2-chloro-5-piperidin-4-ylethynyl-phenyl)-4,5-dihydrothiazolo[4,5-h]quinazolin-2-yl]-acetamide

2.0 g (4.0 mmol)N-[8-(2-chloro-5-iod-phenyl)-4,5-dihydro-thiazolo[4,5-h]quinazolin-2-yl]-acetamideare placed in 50 mL tetrahydrofuran under an argon atmosphere andcombined with 1.5 g (7 mmol) tert-butyl4-ethynyl-piperidine-1-carboxylate and 0.5 ml (3 mmol)diisopropylethylamine. The mixture is kept free from oxygen and 78 mg(0.1 mmol) triphenylphosphine palladium(II)-chloride and 21 mg (0.1mmol) copper(I)-iodide are added. The mixture is stirred for 5 hours at80° C. After cooling to ambient temperature the reaction mixture iscombined with dichloromethane and washed with dilute ammonia solution.The organic phase is dried and evaporated to dryness. The residue ispurified by chromatography, corresponding fractions are combined andfreeze-dried. The intermediate product obtained is stirred for 2 hoursin ethereal hydrochloric acid, suction filtered and dried. Yield: 65 mg(m.p.: 162° C.; MH+=430; RT=3.72; Method A)

Example 156N-{8-[5-(1-acetyl-piperidin-4-ylethynyl)-2-chloro-phenyl]-4,5-dihydro-thiazolo[4,5-h]quinazolin-2-yl}-acetamide

7 μl acetic acid and 50 mg (0.16 mmol)O-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate(TBTU) are placed in 5 mL dichloromethane, combined with 32 μldiisopropylethylamine and stirred for 0.5 hours at ambient temperature.60 mg (0.13 mmol)N-[8-(2-chloro-5-piperidin-4-ylethynyl-phenyl)-4,5-dihydro-thiazolo[4,5-h]quinazolin-2-yl]-acetamide(Example 155) are added, then the mixture is stirred for 16 hours atambient temperature. Then the reaction mixture is extracted withpotassium carbonate solution and dichloromethane. The organic phase isdried and evaporated to dryness. The residue is purified bychromatography.

Yield: 15 mg (MH+=506; RT=2.87; Method A)

The following Examples may be prepared analogously:

TABLE 6

HPLC-MS Example R¹ R^(2a) R^(2b) R⁴ R³ analysis 156 H₃C—X₁

H H

MH+ = 506 RT = 2.87 Method A 157 H₃C—X₁

H H

MH+ = 534 RT = 3.19 Method A 158 H₃C—X₁

H H

MH+ = 548 RT = 3.29 Method A 159 H₃C—X₁

H H

MH+ = 560 RT = 3.45 Method A 160 H₃C—X₁

H H

MH+ = 574 RT = 3.45 Method A

Example 161N-{8-[2-chloro-5-(1-methanesulphonyl-piperidin-4-ylethynyl)-phenyl]-4,5-dihydro-thiazolo[4,5-h]quinazolin-2-yl}-acetamide

A mixture of 50 mg (0.11 mmol)N-[8-(2-chloro-5-piperidin-4-ylethynyl-phenyl)-4,5-dihydro-thiazolo[4,5-h]quinazolin-2-yl]-acetamide,65 μL triethylamine and 15 μL methanesulphonic acid chloride in 1 mLdichloromethane is stirred for three hours at ambient temperature. Thereaction mixture is washed with saturated aqueous sodium hydrogencarbonate solution and the organic phase is evaporated down. The residueremaining is purified by RP-HPLC. Yield: 23 mg yellow solid (MH+=542;RT=3.07; Method A)

The following Examples may be prepared analogously:

TABLE 7

HPLC-MS Example R¹ R^(2a) R^(2b) R⁴ R³ analysis 161 H₃C—X₁

H H

MH+ = 542 RT = 3.07 Method A 162 H₃C—X₁

H H

MH+ = 571 RT = 3.23 Method A 163 H₃C—X₁

H H

MH+ = 568 RT = 3.21 Method A 164 H₃C—X₁

H H

MH+ = 570 RT = 3.23 Method A

Example 1654-[3-(2-acetylamino-4,5-dihydro-thiazolo[4,5-h]quinazolin-8-yl)-4-chloro-phenylethynyl]-piperidine-1-carboxylicacid isopropylamide

50 mg (0.11 mmol)N-[8-(2-chloro-5-piperidin-4-ylethynyl-phenyl)-4,5-dihydrothiazolo[4,5-h]quinazolin-2-yl]-acetamideare suspended in 1 mL acetonitrile and combined successively with 17 μLtriethylamine and 22 μM isopropyl isocyanate. The yellow suspension isstirred for three hours at ambient temperature and then washed withaqueous potassium carbonate solution. The organic phase is evaporateddown and the residue is purified by RP-HPLC. Yield: 30 mg yellow solid.

The following Examples may be prepared analogously by using thecorresponding isocyanates or carbamoyl chlorides:

TABLE 8

HPLC-MS Example R¹ R^(2a) R^(2b) R⁴ R³ analysis 165 H₃C—X₁

H H

MH+ = 549 RT = 3.09 Method A 166 H₃C—X₁

H H

MH+ = 535 RT = 2.89 Method A 167 H₃C—X₁

H H

MH+ = 521 RT = 2.84 Method A 168 H₃C—X₁

H H

MH+ = 563 RT = 3.28 Method A 169 H₃C—X₁

H H

MH+ = 535 RT = 3.08 Method A 170 H₃C—X₁

H H

MH+ = 603 RT = 3.44 Method A 171 H₃C—X₁

H H

MH+ = 575 RT = 3.19 Method A 172 H₃C—X₁

H H

MH+ = 561 RT = 3.18 Method A 173 H₃C—X₁

H H

MH+ = 577 RT = 2.99 Method A

Example 174N-{8-[2-chloro-5-(5-morpholin-4-yl-pent-1-ynyl)-phenyl]-4,5-dihydro-thiazolo[4,5-h]quinazolin-2-yl}-acetamide

5.0 g (10.4 mmol)N-[8-(2-chloro-5-iodo-phenyl)-4,5-dihydro-thiazolo[4,5-h]quinazolin-2-yl]-acetamideare placed in 100 mL tetrahydrofuran under an argon atmosphere andcombined with 3.5 g (41.4 mmol) 4-pentyn-1-ol and 6.7 ml (41.4 mmol)diisopropylethylamine. The mixture is kept free from oxygen and 727 mg(1.0 mmol) triphenylphosphine palladium(II)-chloride and 197 mg (1.0mmol) copper(I)-iodide are added. The mixture is stirred for 2.5 hoursat ambient temperature. After cooling to ambient temperature thereaction mixture is evaporated down and stirred with dichloromethane.The orange precipitate is suction filtered and dried. Yield: 5.2 g

5.2 g (10.3 mmol) of the intermediate described above, 3.9 mL (28.1mmol) triethylamine and 40 mg 4-dimethylaminopyridine in 40 mL THF iscombined at 0° C. with 1.8 mL (23.4 mmol) methanesulphonyl chloride andstirred overnight at ambient temperature. The reaction mixture isevaporated down and taken up in aqueous ammonia and dichloromethane. Theorganic phase is filtered through activated charcoal, dried andevaporated down. The residue is purified by MPLC(dichloromethane/methanol 100:5).

Yield: 2.2 g colourless oil.

80 mg (0.16 mmol) of the intermediate described above and 40 mg (0.46mmol) morpholine in 1 mL DMF are stirred overnight at ambienttemperature and the heated to 70° C. for six hours. The reaction mixtureis purified by RP-HPLC without any further working up. Yield: 58 mgyellow solid (MH+=508; RT=2.46; Method A)

TABLE 9

HPLC-MS Example R¹ R^(2a) R^(2b) R⁴ R³ analysis 174 H₃C—X₁

H H

MH+ = 508 RT = 2.46 Method A 175 H₃C—X₁

H H

MH+ = 506 RT = 2.62 Method A 176 H₃C—X₁

H H

MH+ = 494 RT = 2.61 Method A 177 H₃C—X₁

H H

MH+ = 480 RT = 2.51 Method A 178 H₃C—X₁

H H

MH+ = 492 RT = 2.52 Method A 179 H₃C—X₁

H H

MH+ = 466 RT = 2.45 Method A 180 H₃C—X₁

H H

MH+ = 494 RT = 2.53 Method A 181 H₃C—X₁

H H

MH+ = 535 RT = 2.29 Method A 182 H₃C—X₁

H H

MH+ = 521 RT = 2.29 Method A 183 H₃C—X₁

H H

MH+ = 549 RT = 2.31 Method A

Biological Test

The compounds of formula (I) mentioned by way of example arecharacterised by an affinity for PI3-kinase, i.e. in the test by an IC₅₀value of below 600 nmol/litre.

In order to determine the inhibitory activity of the compounds on PI3Kγ,the in-vitro kinase assay described below was used. The expression andpurification of Gβ₁γ₂-His and p101-GST/p110γ from Sf9-cells (Spodopterafrugiperda 9) has already been described (Maier et al., J. Biol. Chem.1999 (274) 29311-29317).

10 μl of the compound to be tested were placed on 96 well PVDF filterplates (0.45 μM) and incubated for 20 min with 30 μl lipid vesicles(PIP₂ (0.7 μg/well), phosphatidylethanolamine (7.5 μg/well),phosphatidylserine (7.5 μg/well), sphingomyelin (0.7 μg/well) andphosphatidylcholine (3.2 μg/well)) which contained 1-3 ng PI3K□ and20-60 ng G□₁□₂-His. The reaction was started by the addition of 10 μlreaction buffer (40 mM Hepes, pH 7.5, 100 mM NaCl, 1 mM EGTA, 1 mM□-glycerophosphate, 1 mM DTT, 7 mM MgCl₂ and 0.1% BSA; 1 μM ATP and 0.2μCi [□-³³P]ATP) and incubated for 120 min at ambient temperature. Thereaction solution was sucked through the filters by the application of avacuum and washed with 200 μl PBS. After the plates had been dried at50° C. the radioactivity remaining in the plates was determined afterthe addition of 50 μl scintillation liquid using a Top-Count measuringdevice.

Ranges of Indications

It has been found that the compounds of formula (I) are characterised bya variety of possible applications in the therapeutic field. Particularmention should be made of those applications for which the compounds offormula (I) according to the invention are preferably used by virtue oftheir pharmaceutical activity as PI3-kinase modulators.

Generally speaking, these are diseases in whose pathology PI3-kinasesare implicated, particularly inflammatory and allergic diseases.Particular mention should be made of inflammatory and allergicrespiratory complaints, inflammatory diseases of the gastrointestinaltract, inflammatory diseases of the motor apparatus, inflammatory andallergic skin diseases, inflammatory eye diseases, diseases of the nasalmucosa, inflammatory or allergic ailments which involve autoimmunereactions or inflammation of the kidneys. The treatment may besymptomatic, adaptive, curative or preventative.

Respiratory complaints deserving special mention would be chronic and/orobstructive respiratory complaints. The compounds of formula I accordingto the invention may, by virtue of their pharmacological properties,bring about a reduction in

-   -   Tissue damage    -   Inflammation of the airways    -   bronchial hyperreactivity    -   the process of reconstruction of the lung as a result of        inflammation    -   worsening of the disease (progression).

The compounds according to the invention are particularly preferred forpreparing a medicament for the treatment of chronic bronchitis, acutebronchitis, bronchitis caused by bacterial or viral infection or fungior helminths, allergic bronchitis, toxic bronchitis, chronic obstructivebronchitis (COPD), asthma (intrinsic or allergic), paediatric asthma,bronchiectasis, allergic alveolitis, allergic or non-allergic rhinitis,chronic sinusitis, cystic fibrosis or mucoviscidosis,alpha-1-antitrypsin deficiency, cough, pulmonary emphysema, interstitiallung diseases such as e.g. pulmonary fibrosis, asbestosis and silicosisand alveolitis; hyperreactive airways, nasal polyps, pulmonary oedemasuch as e.g. toxic pulmonary oedema and ARDS/IRDS, pneumonitis ofdifferent origins, e.g. radiation-induced or caused by aspiration orinfectious pneumonitis, collagenoses such as lupus erythematodes,systemic sclerodermy, sarcoidosis or Boeck's disease.

The compounds of formula (I) are also suitable for the treatment ofdiseases of the skin, such as e.g. psoriasis, contact dermatitis, atopicdermatitis, alopecia greata (circular hair loss), erythema exsudativummultiforme (Stevens-Johnson Syndrome), dermatitis herpetiformis,sclerodermy, vitiligo, nettle rash (urticaria), lupus erythematodes,follicular and surface pyodermy, endogenous and exogenous acne, acnerosacea and other inflammatory or allergic or proliferative skindiseases.

Moreover, the compounds of formula (I) are suitable for therapeutic usein cases of inflammatory or allergic complaints which involve autoimmunereactions, such as e.g. inflammatory bowel diseases, e.g. Crohn'sdisease or ulcerative colitis; diseases of the arthritis type, such ase.g. rheumatoid or psoriatic arthritis, osteoarthritis, rheumatoidspondylitis and other arthritic conditions or multiple sclerosis.

The following general inflammatory or allergic diseases may also bementioned, which can be treated with medicaments containing compounds offormula (I):

-   -   inflammation of the eye, such as e.g. conjunctivitis of various        kinds, e.g. caused by infections with fungi or bacteria,        allergic conjunctivitis, irritable conjunctivitis, drug-induced        conjunctivitis, keratitis, uveitis    -   diseases of the nasal mucosa, such as e.g. allergic        rhinitis/sinusitis or nasal polyps    -   inflammatory or allergic conditions, such as e.g. systemic lupus        erythematodes, chronic hepatitis, kidney inflammations such as        glomerulonephritis, interstitial nephritis or idiopathic        nephrotic syndrome.

Other diseases which may be treated with a drug containing compounds offormula (I) on the basis of their pharmacological activity include toxicor septic shock syndrome, atherosclerosis, middle ear infections (otitismedia), hypertrophy of the heart, cardiac insufficiency, stroke,ischaemic reperfusion injury or neurodegenerative diseases such asParkinson's disease or Alzheimer's.

Combinations

The compounds of formula (I) may be used on their own or in combinationwith other active substances of formula (I). If desired the compounds offormula (I) may also be used in combination with W, where W denotes apharmacologically active substance and (for example) is selected fromamong the betamimetics, anticholinergics, corticosteroids,PDE4-inhibitors, LTD4-antagonists, EGFR-inhibitors, dopamine agonists,H1-antihistamines, PAF-antagonists and PI3-kinase inhibitors, preferablyPI3-{tilde over (□)}Kinase inhibitors. Moreover, double or triplecombinations of W may be combined with the compounds of formula (I).Combinations of W might be, for example:

-   -   W denotes a betamimetic, combined with an active substance        selected from among the anticholinergics, corticosteroids,        PDE4-inhibitors, EGFR-inhibitors and LTD4-antagonists,    -   W denotes an anticholinergic, combined with an active substance        selected from among the betamimetics, corticosteroids,        PDE4-inhibitors EGFR-inhibitors and LTD4-antagonists,    -   W denotes a corticosteroid, combined with an active substance        selected from among the PDE4-inhibitors, EGFR-inhibitors and        LTD4-antagonists    -   W denotes a PDE4-inhibitor, combined with an active substance        selected from among the EGFR-inhibitors and LTD4-antagonists    -   W denotes an EGFR-inhibitor, combined with an LTD4-antagonist.

The compounds used as betamimetics are preferably compounds selectedfrom among albuterol, arformoterol, bambuterol, bitolterol, broxaterol,carbuterol, clenbuterol, fenoterol, formoterol, hexoprenaline, ibuterol,isoetharine, isoprenaline, levosalbutamol, mabuterol, meluadrine,metaproterenol, orciprenaline, pirbuterol, procaterol, reproterol,rimiterol, ritodrine, salmefamol, salmeterol, soterenol, sulphonterol,terbutaline, tiaramide, tolubuterol, zinterol, CHF-1035, HOKU-81,KUL-1248 and

-   3-(4-{6-[2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-hexyloxy}-butyl)-benzyl-sulphonamide-   5-[2-(5.6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinoline-2-one-   4-hydroxy-7-[2-{[2-{[3-(2-phenylethoxy)propyl]sulphonyl}ethyl]amino}ethyl]-2(3H)-benzothiazolone-   1-(2-fluoro-4-hydroxyphenyl)-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino]ethanol-   1-[3-(4-methoxybenzyl-amino)-4-hydroxyphenyl]-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino]ethanol-   1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-N,N-dimethylaminophenyl)-2-methyl-2-propylamino]ethanol-   1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-methoxyphenyl)-2-methyl-2-propylamino]ethanol-   1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-n-butyloxyphenyl)-2-methyl-2-propylamino]ethanol-   1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-{4-[3-(4-methoxyphenyl)-1,2,4-triazole-3-yl]-2-methyl-2-butylamino}ethanol-   5-hydroxy-8-(1-hydroxy-2-isopropylaminobutyl)-2H-1,4-benzoxazin-3-(4H)-on-   1-(4-amino-3-chloro-5-trifluoromethylphenyl)-2-tert.-butylamino)ethanol-   6-hydroxy-8-{1-hydroxy-2-[2-(4-methoxy-phenyl)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one-   6-hydroxy-8-{1-hydroxy-2-[2-(ethyl    4-phenoxy-acetate)-1,1-dimethylethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one-   6-hydroxy-8-{1-hydroxy-2-[2-(4-phenoxy-acetic    acid)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one-   8-{2-[1,1-dimethyl-2-(2.4.6-trimethylphenyl)-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one-   6-hydroxy-8-{1-hydroxy-2-[2-(4-hydroxy-phenyl)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one-   6-hydroxy-8-{1-hydroxy-2-[2-(4-isopropyl-phenyl)-1.1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one-   8-{2-[2-(4-ethyl-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one-   8-{2-[2-(4-ethoxy-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one-   4-(4-{2-[2-hydroxy-2-(6-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-ethylamino]-2-methyl-propyl}-phenoxy)-butyric    acid-   8-{2-[2-(3,4-difluoro-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one-   1-(4-ethoxy-carbonylamino-3-cyano-5-fluorophenyl)-2-(tert-butylamino)ethanol    optionally in the form of the racemates, enantiomers, diastereomers    thereof and optionally in the form of the pharmacologically    acceptable acid addition salts, solvates or hydrates thereof.    According to the invention the acid addition salts of the    betamimetics are preferably selected from among the hydrochloride,    hydrobromide, hydriodide, hydrosulphate, hydrophosphate,    hydromethanesulphonate, hydronitrate, hydromaleate, hydroacetate,    hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate,    hydrosuccinate, hydrobenzoate and hydro-p-toluenesulphonate.

The anticholinergics used are preferably compounds selected from amongthe tiotropium salts, preferably the bromide salt, oxitropium salts,preferably the bromide salt, flutropium salts, preferably the bromidesalt, ipratropium salts, preferably the bromide salt, glycopyrroniumsalts, preferably the bromide salt, trospium salts, preferably thechloride salt, tolterodine. In the above-mentioned salts the cations arethe pharmacologically active constituents. As anions the above-mentionedsalts may preferably contain the chloride, bromide, iodide, sulphate,phosphate, methanesulphonate, nitrate, maleate, acetate, citrate,fumarate, tartrate, oxalate, succinate, benzoate or p-toluenesulphonate,while chloride, bromide, iodide, sulphate, methanesulphonate orp-toluenesulphonate are preferred as counter-ions.

Of all the salts the chlorides, bromides, iodides and methanesulphonatesare particularly preferred.

Other specified compounds are:

-   tropenol 2,2-diphenylpropionate methobromide-   scopine 2,2-diphenylpropionate methobromide-   scopine 2-fluoro-2,2-diphenylacetate methobromide-   tropenol 2-fluoro-2,2-diphenylacetate methobromide-   tropenol 3,3′,4,4′-tetrafluorobenzilate methobromide-   scopine 3,3′,4,4′-tetrafluorobenzilate methobromide-   tropenol 4,4′-difluorobenzilate methobromide-   scopine 4,4′-difluorobenzilate methobromide-   tropenol 3,3′-difluorobenzilate methobromide-   scopine 3,3′-difluorobenzilate methobromide-   tropenol 9-hydroxy-fluorene-9-carboxylate methobromide-   tropenol 9-fluoro-fluorene-9-carboxylate methobromide-   scopine 9-hydroxy-fluorene-9-carboxylate methobromide-   scopine 9-fluoro-fluorene-9-carboxylate methobromide-   tropenol 9-methyl-fluorene-9-carboxylate methobromide-   scopine 9-methyl-fluorene-9-carboxylate methobromide-   cyclopropyltropine benzilate methobromide-   cyclopropyltropine 2,2-diphenylpropionate methobromide-   cyclopropyltropine 9-hydroxy-xanthene-9-carboxylate methobromide-   cyclopropyltropine 9-methyl-fluorene-9-carboxylate methobromide-   cyclopropyltropine 9-methyl-xanthene-9-carboxylate methobromide-   cyclopropyltropine 9-hydroxy-fluorene-9-carboxylate methobromide-   cyclopropyltropine methyl 4,4′-difluorobenzilate methobromide-   tropenol 9-hydroxy-xanthene-9-carboxylate methobromide-   scopine 9-hydroxy-xanthene-9-carboxylate methobromide-   tropenol 9-methyl-xanthene-9-carboxylate-methobromide-   scopine 9-methyl-xanthene-9-carboxylate-methobromide-   tropenol 9-ethyl-xanthene-9-carboxylate methobromide-   tropenol 9-difluoromethyl-xanthene-9-carboxylate methobromide-   scopine 9-hydroxymethyl-xanthene-9-carboxylate methobromide

As corticosteroids it is preferable to use compounds selected from amongprednisolone, prednisone, butixocort propionate, flunisolide,beclomethasone, triamcinolone, budesonide, fluticasone, mometasone,ciclesonide, rofleponide, dexamethasone, betamethasone, deflazacort,RPR-106541, NS-126, ST-26 and

-   (S)-fluoromethyl    6,9-difluoro-17-[(2-furanylcarbonyl)oxy]-11-hydroxy-16-methyl-3-oxo-androsta-1,4-diene-17-carbothionate-   (S)-(2-oxo-tetrahydro-furan-3S-yl)6,9-difluoro-11-hydroxy-16-methyl-3-oxo-17-propionyloxy-androsta-1,4-diene-17-carbothionate,-   etiprednol-dichloroacetate    optionally in the form of the racemates, enantiomers or    diastereomers thereof and optionally in the form of the salts and    derivatives thereof, the solvates and/or hydrates thereof. Any    reference to steroids includes a reference to any salts or    derivatives, hydrates or solvates thereof which may exist. Examples    of possible salts and derivatives of the steroids may be: alkali    metal salts, such as for example sodium or potassium salts,    sulphobenzoates, phosphates, isonicotinates, acetates, propionates,    dihydrogen phosphates, palmitates, pivalates or furoates.

PDE4-inhibitors which may be used are preferably compounds selected fromamong enprofyllin, theophyllin, roflumilast, ariflo (cilomilast),tofimilast, pumafentrin, lirimilast, arofyllin, atizoram, D-4418,Bay-198004, BY343, CP-325.366, D-4396 (Sch-351591), AWD-12-281(GW-842470), NCS-613, CDP-840, D-4418, PD-168787, T-440, T-2585,V-11294A, CI-1018, CDC-801, CDC-3052, D-22888, YM-58997, Z-15370 and

-   N-(3,5-dichloro-1-oxo-pyridin-4-yl)-4-difluoromethoxy-3-cyclopropylmethoxybenzamide-   (−)_(p)-[(4aR*,10bS*)-9-ethoxy-1,2,3,4,4a,10b-hexahydro-8-methoxy-2-methylbenzo[s][1,6]naphthyridin-6-yl]-N,N-diisopropylbenzamide-   (R)-(+)-1-(4-bromobenzyl)-4-[(3-cyclopentyloxy)-4-methoxyphenyl]-2-pyrrolidone-   3-(cyclopentyloxy-4-methoxyphenyl)-1-(4-N′-[N-2-cyano-S-methylisothioureido]benzyl)-2-pyrrolidone-   cis[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylic    acid]-   2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-one-   cis[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-ol]-   (R)-(+)-ethyl[4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidin-2-ylidene]acetate-   (S)-(−)-ethyl[4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidin-2-ylidene]acetate-   9-cyclopentyl-5,6-dihydro-7-ethyl-3-(2-thienyl)-9H-pyrazolo[3,4-c]-1,2,4-triazolo[4.3-a]pyridine-   9-cyclopentyl-5,6-dihydro-7-ethyl-3-(tert-butyl)-9H-pyrazolo[3,4-c]-1,2,4-triazolo[4.3-a]pyridine    optionally in the form of the racemates, enantiomers or    diastereomers thereof and optionally in the form of the    pharmacologically acceptable acid addition salts thereof, the    solvates and/or hydrates thereof. According to the invention the    acid addition salts of the betamimetics are preferably selected from    among the hydrochloride, hydrobromide, hydriodide, hydrosulphate,    hydrophosphate, hydromethanesulphonate, hydronitrate, hydromaleate,    hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate,    hydroxalate, hydrosuccinate, hydrobenzoate and    hydro-p-toluenesulphonate.

The LTD4-antagonists used are preferably compounds selected from amongmontelukast, pranlukast, zafirlukast, MCC-847 (ZD-3523), MN-001,MEN-91507 (LM-1507), VUF-5078, VUF-K-8707, L-733321 and

-   1-(((R)-(3-(2-(6,7-difluoro-2-quinolinyl)ethenyl)phenyl)-3-(2-(2-hydroxy-2-propyl)phenyl)thio)methylcyclopropane-acetic    acid,-   1-(((1(R)-3(3-(2-(2,3-dichlorothieno[3,2-b]pyridin-5-yl)-(E)-ethenyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)cyclopropaneacetic    acid-   [2-[[2-(4-tert-butyl-2-thiazolyl)-5-benzofuranyl]oxymethyl]phenyl]acetic    acid    optionally in the form of the racemates, enantiomers or    diastereomers thereof and optionally in the form of the    pharmacologically acceptable acid addition salts, solvates and/or    hydrates thereof. According to the invention the acid addition salts    of the betamimetics are preferably selected from among the    hydrochloride, hydrobromide, hydroiodide, hydrosulphate,    hydrophosphate, hydromethanesulphonate, hydronitrate, hydromaleate,    hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate,    hydroxalate, hydrosuccinate, hydrobenzoate and    hydro-p-toluenesulphonate. By salts or derivatives which the    LTD4-antagonists may optionally be capable of forming are meant, for    example: alkali metal salts, such as for example sodium or potassium    salts, alkaline earth metal salts, sulphobenzoates, phosphates,    isonicotinates, acetates, propionates, dihydrogen phosphates,    palmitates, pivalates or furoates.

EGFR-inhibitors which may be used are preferably compounds selected fromamong cetuximab, trastuzumab, ABX-EGF, Mab ICR-62 and

-   4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]-amino}-7-cyclopropylmethoxy-quinazoline-   4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-diethylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline-   4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline-   4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopentyloxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((R)-2-methoxymethyl-6-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-((S)-6-methyl-2-oxo-morpholin-4-yl)-ethoxy]-7-methoxy-quinazoline-   4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline-   4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclopentyloxy-quinazoline-   4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-(N,N-bis-(2-methoxy-ethyl)-amino)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline-   4-[(R)-(1-phenyl-ethyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-ethyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline-   4-[(R)-(1-phenyl-ethyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline-   4-[(R)-(1-phenyl-ethyl)amino]-6-({4-[N-(tetrahydropyran-4-yl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline-   4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-((R)-tetrahydrofuran-3-yloxy)-quinazoline-   4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline-   4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopentyloxy-quinazoline-   4-[(3-chloro-4-fluorophenypamino]-6-{[4-(N-cyclopropyl-N-methyl-amino)-1-oxo-2-buten-1-yl]amino}-7-cyclopentyloxy-quinazoline-   4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-[(R)-(tetrahydrofuran-2-yl)methoxy]-quinazoline-   4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline-   4-[(3-ethynyl-phenyl)amino]-6.7-bis-(2-methoxy-ethoxy)-quinazoline-   4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(morpholin-4-yl)-propyloxy]-6-[(vinylcarbonyl)amino]-quinazoline-   4-[(R)-(1-phenyl-ethyl)amino]-6-(4-hydroxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidine-   3-cyano-4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-ethoxy-quinoline-   4-{[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]amino}-6-(5-{[(2-methanesulphonyl-ethyl)amino]methyl}-furan-2-yl)quinazoline-   4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-methoxy-quinazoline-   4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]-amino}-7-[(tetrahydrofuran-2-yl)methoxy]-quinazoline-   4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N,N-bis-(2-methoxy-ethyl)-amino]-1-oxo-2-buten-1-yl}amino)-7-[(tetrahydrofuran-2-yl)methoxy]-quinazoline-   4-[(3-ethynyl-phenyl)amino]-6-{[4-(5.5-dimethyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2.2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2.2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-7-[(R)-(tetrahydrofuran-2-yl)methoxy]-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-7-[2-(2.2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-6-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{2-[4-(2-oxo-morpholin-4-yl)-piperidin-1-yl]-ethoxy}-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(tert.-butyloxycarbonyl)-piperidin-4-yloxy]-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-amino-cyclohexan-1-yloxy)-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-methanesulphonylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-3-yloxy)-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(methoxymethyl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(piperidin-3-yloxy)-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(2-acetylamino-ethyl)-piperidin-4-yloxy]-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-ethoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-((S)-tetrahydrofuran-3-yloxy)-7-hydroxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-methoxy-ethoxy)-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(dimethylamino)sulphonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(morpholin-4-yl)carbonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(morpholin-4-yl)sulphonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-acetylamino-ethoxy)-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-methanesulphonylamino-ethoxy)-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(piperidin-1-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-aminocarbonyl    methyl-piperidin-4-yloxy)-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(tetrahydropyran-4-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(morpholin-4-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(morpholin-4-yl)sulphonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-ethansulphonylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-ethoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-(2-methoxy-ethoxy)-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(2-methoxy-acetyl)-piperidin-4-yloxy]-7-(2-methoxy-ethoxy)-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-acetylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline-   4-[(3-ethynyl-phenyl)amino]-6-[1-(tert.-butyloxycarbonyl)-piperidin-4-yloxy]-7-methoxy-quinazoline-   4-[(3-ethynyl-phenyl)amino]-6-(tetrahydropyran-4-yloxy]-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(piperidin-1-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(4-methyl-piperazin-1-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{cis-4-[(morpholin-4-yl)carbonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[2-(2-oxopyrrolidin-1-yl)ethyl]-piperidin-4-yloxy}-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-(2-methoxy-ethoxy)-quinazoline-   4-[(3-ethynyl-phenyl)amino]-6-(1-acetyl-piperidin-4-yloxy)-7-methoxy-quinazoline-   4-[(3-ethynyl-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-methoxy-quinazoline-   4-[(3-ethynyl-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7(2-methoxy-ethoxy)-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-isopropyloxycarbonyl-piperidin-4-yloxy)-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-methylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{cis-4-[N-(2-methoxy-acetyl)-N-methyl-amino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline-   4-[(3-ethynyl-phenyl)amino]-6-(piperidin-4-yloxy)-7-methoxy-quinazoline-   4-[(3-ethynyl-phenyl)amino]-6-[1-(2-methoxy-acetyl)-pipenclin-4-yloxy]-7-methoxy-quinazoline-   4-[(3-ethynyl-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-pipericlin-4-yloxy}-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(cis-2,6-dimethyl-morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(2-methyl-morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(S,S)-(2-oxa-5-aza-bicyclo[2,2,1]hept-5-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(N-methyl-N-2-methoxyethyl-amino)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-ethyl-piperidin-4-yloxy)-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(2-methoxyethyl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(3-methoxypropyl-amino)-carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-methanesulphonyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-acetyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-methylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-[trans-4-(N-methanesulphonyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-dimethylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-{N-[(morpholin-4-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2.2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-7-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-cyano-piperidin-4-yloxy)-7-methoxy-quinazoline    optionally in the form of the racemates, enantiomers, diastereomers    thereof and optionally in the form of the pharmacologically    acceptable acid addition salts, solvates or hydrates thereof.    According to the invention the preferred acid addition salts of the    betamimetics are selected from among the hydrochloride,    hydrobromide, hydriodide, hydrosulphate, hydrophosphate,    hydromethanesulphonate, hydronitrate, hydromaleate, hydroacetate,    hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate,    hydrosuccinate, hydrobenzoate and hydro-p-toluenesulphonate.

The dopamine agonists used are preferably compounds selected from amongbromocriptin, cabergoline, alpha-dihydroergocryptine, lisuride,pergolide, pramipexol, roxindol, ropinirol, talipexol, tergurid andviozan, optionally in the form of the racemates, enantiomers,diastereomers thereof and optionally in the form of thepharmacologically acceptable acid addition salts, solvates or hydratesthereof. According to the invention the preferred acid addition salts ofthe betamimetics are selected from among the hydrochloride,hydrobromide, hydriodide, hydrosulphate, hydrophosphate,hydromethanesulphonate, hydronitrate, hydromaleate, hydroacetate,hydrocitrate, hydrofumarate, hydrotartrate, hydrooxalate,hydrosuccinate, hydrobenzoate and hydro-p-toluenesulphonate.

H1-Antihistamines which may be used are preferably compounds selectedfrom among epinastine, cetirizine, azelastine, fexofenadine,levocabastine, loratadine, mizolastine, ketotifen, emedastine,dimetindene, clemastine, bamipine, cexchlorpheniramine, pheniramine,doxylamine, chlorophenoxamine, dimenhydrinate, diphenhydramine,promethazine, ebastine, desloratidine and meclozine, optionally in theform of the racemates, enantiomers, diastereomers thereof and optionallyin the form of the pharmacologically acceptable acid addition salts,solvates or hydrates thereof. According to the invention the preferredacid addition salts of the betamimetics are selected from among thehydrochloride, hydrobromide, hydriodide, hydrosulphate, hydrophosphate,hydromethanesulphonate, hydronitrate, hydromaleate, hydroacetate,hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate,hydrobenzoate and hydro-p-toluenesulphonate.

The PAF-antagonists used are preferably compounds selected from among

-   4-(2-chlorophenyl)-9-methyl-2-[3(4-morpholinyl)-3-propanon-1-yl]-6H-thieno-[3,2-f]-[1,2,4]triazolo[4,3-a][1,4]diazepine-   6-(2-chlorophenyl)-8,9-dihydro-1-methyl-8-[(4-morpholinyl)carbonyl]-4H,7H-cyclo-penta-[4,5]thieno-[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine,    optionally in the form of the racemates, enantiomers, diastereomers    thereof and optionally in the form of the pharmacologically    acceptable acid addition salts, solvates or hydrates thereof.    According to the invention the preferred acid addition salts of the    betamimetics are selected from among the hydrochloride,    hydrobromide, hydriodide, hydrosulphate, hydrophosphate,    hydromethanesulphonate, hydronitrate, hydromaleate, hydroacetate,    hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate,    hydrosuccinate, hydrobenzoate and hydro-p-toluenesulphonate.

The PI3-kinase-δ-inhibitors used are preferably compounds selected fromamong: IC87114,2-(6-aminopurin-9-ylmethyl)-3-(2-chlorophenyl)-6.7-dimethoxy-3H-quinazolin-4-one;2-(6-aminopurin-o-ylmethyl)-6-bromo-3-(2-chlorophenyl)-3H-quinazolin-4-one;2-(6-aminopurin-o-ylmethyl)-3-(2-chlorophenyl)-7-fluoro-3H-quinazolin-4-one;2-(6-aminopurin-9-ylmethyl)-6-chloro-3-(2-chlorophenyl)-3H-quinazolin-4-one;2-(6-aminopurin-9-ylmethyl)-3-(2-chlorophenyl)-5-fluoro-3H-quinazolin-4-one;2-(6-aminopurin-o-ylmethyl)-5-chloro-3-(2-chloro-phenyl)-3H-quinazolin-4-one;2-(6-aminopurin-9-ylmethyl)-3-(2-chlorophenyl)-5-methyl-3H-quinazolin-4-one;2-(6-aminopurin-9-ylmethyl)-8-chloro-3-(2-chlorophenyl)-3H-quinazolin-4-one;2-(6-aminopurin-9-ylmethyl)-3-biphenyl-2-yl-5-chloro-3H-quinazolin-4-one;5-chloro-2-(9H-purin-6-ylsulphanylmethyl)-3-o-tolyl-3H-quinazolin-4-one;5-chloro-3-(2-fluorophenyl)-2-(9H-purin-6-yl-sulphanylmethyl)-3H-quinazolin-4-one;2-(6-aminopurin-9-ylmethyl)-5-chloro-3-(2-fluorophenyl)-3H-quinazolin-4-one;3-biphenyl-2-yl-5-chloro-2-(9H-purin-6-ylsulphanylmethyl)-3H-quinazolin-4-one;5-chloro-3-(2-methoxyphenyl)-2-(9H-purin-6-yl-sulphanylmethyl)-3H-quinazolin-4-one;3-(2-chlorophenyl)-5-fluoro-2-(9H-purin-6-yl-sulphanylmethyl)-3H-quinazolin-4-one;3-(2-chlorophenyl)-6.7-dimethoxy-2-(9H-purin-6-yl-sulphanylmethyl)-3H-quinazolin-4-one;6-bromo-3-(2-chlorophenyl)-2-(9H-purin-6-yl-sulphanylmethyl)-3H-quinazolin-4-one;3-(2-chlorophenyl)-8-trifluoromethyl-2-(9H-purin-6-ylsulphanylmethyl)-3H-quinazolin-4-one;3-(2-chlorophenyl)-2-(9H-purin-6-ylsulphanylmethyl)-3H-benzo[g]quinazolin-4-one;6-chloro-3-(2-chlorophenyl)-2-(9H-purin-6-yl-sulphanylmethyl)-3H-quinazolin-4-one;8-chloro-3-(2-chlorophenyl)-2-(9H-purin-6-yl-sulphanylmethyl)-3H-quinazolin-4-one;3-(2-chlorophenyl)-7-fluoro-2-(9H-purin-6-yl-sulphanylmethyl)-3H-quinazolin-4-one;3-(2-chlorophenyl)-7-nitro-2-(9H-purin-6-yl-sulphanylmethyl)-3H-quinazolin-4-one;3-(2-chlorophenyl)-6-hydroxy-2-(9H-purin-6-yl-sulphanylmethyl)-3H-quinazolin-4-one;5-chloro-3-(2-chlorophenyl)-2-(9H-purin-6-yl-sulphanylmethyl)-3H-quinazolin-4-one;3-(2-chlorophenyl)-5-methyl-2-(9H-purin-6-yl-sulphanylmethyl)-3H-quinazolin-4-one;3-(2-chlorophenyl)-6.7-difluoro-2-(9H-purin-6-yl-sulphanylmethyl)-3H-quinazolin-4-one;3-(2-chlorophenyl)-6-fluoro-2-(9H-purin-6-yl-sulphanylmethyl)-3H-quinazolin-4-one;2-(6-aminopurin-9-ylmethyl)-3-(2-isopropylphenyl)-5-methyl-3H-quinazolin-4-one;2-(6-aminopurin-9-ylmethyl)-5-methyl-3-o-tolyl-3H-quinazolin-4-one;3-(2-fluorophenyl)-5-methyl-2-(9H-purin-6-yl-sulphanylmethyl)-3H-quinazolin-4-one;2-(6-aminopurin-9-ylmethyl)-5-chloro-3-o-tolyl-3H-quinazolin-4-one;2-(6-aminopurin-9-ylmethyl)-5-chloro-3-(2-methoxy-phenyl)-3H-quinazolin-4-one;2-(2-amino-9H-purin-6-ylsulphanylmethyl)-3-cyclopropyl-5-methyl-3H-quinazolin-4-one;3-cyclopropylmethyl-5-methyl-2-(9H-purin-6-ylsulphanylmethyl)-3H-quinazolin-4-one;2-(6-aminopurin-9-ylmethyl)-3-cyclopropylmethyl-5-methyl-3H-quinazolin-4-one;2-(2-amino-9H-purin-6-ylsulphanylmethyl)-3-cyclopropylmethyl-5-methyl-3H-quinazolin-4-one;5-methyl-3-phenethyl-2-(9H-purin-6-ylsulphanylmethyl)-3H-quinazolin-4-one;2-(2-amino-9H-purin-6-ylsulphanylmethyl)-5-methyl-3-phenethyl-3H-quinazolin-4-one;3-cyclopentyl-5-methyl-2-(9H-purin-6-ylsulphanylmethyl)-3H-quinazolin-4-one;2-(6-aminopurin-9-ylmethyl)-3-cyclopentyl-5-methyl-3H-quinazolin-4-one;3-(2-chloropyridin-3-yl)-5-methyl-2-(9H-purin-6-ylsulphanylmethyl)-3H-quinazolin-4-one;2-(6-aminopurin-9-ylmethyl)-3-(2-chloropyridin-3-yl)-5-methyl-3H-quinazolin-4-one;3-methyl-4-[5-methyl-4-oxo-2-(9H-purin-6-ylsulphanylmethyl)-4H-quinazolin-3-yl]-benzoicacid;3-cyclopropyl-5-methyl-2-(9H-purin-6-ylsulphanylmethyl)-3H-quinazolin-4-one;2-(6-aminopurin-9-ylmethyl)-3-cyclopropyl-5-methyl-3H-quinazolin-4-one;5-methyl-3-(4-nitrobenzyl)-2-(9H-purin-6-ylsulphanylmethyl)-3H-quinazolin-4-one;3-cyclohexyl-5-methyl-2-(9H-purin-6-ylsulphanylmethyl)-3H-quinazolin-4-one;2-(6-aminopurin-9-ylmethyl)-3-cyclohexyl-5-methyl-3H-quinazolin-4-one;2-(2-amino-9H-purin-6-ylsulphanylmethyl)-3-cyclo-hexyl-5-methyl-3H-quinazolin-4-one;5-methyl-3-(E-2-phenylcyclopropyl)-2-(9H-purin-6-ylsulphanylmethyl)-3H-quinazolin-4-one;3-(2-chlorophenyl)-5-fluoro-2-[(9H-purin-6-ylamino)methyl]-3H-quinazolin-4-one;2-[(2-amino-9H-purin-6-ylamino)methyl]-3-(2-chlorophenyl)-5-fluoro-3H-quinazolin-4-one;5-methyl-2-[(9H-purin-6-ylamino)methyl]-3-o-tolyl-3H-quinazolin-4-one;2-[(2-amino-9H-purin-6-ylamino)methyl]-5-methyl-3-o-tolyl-3H-quinazolin-4-one;2-[(2-fluoro-9H-purin-6-ylamino)methyl]-5-methyl-3-o-tolyl-3H-quinazolin-4-one;(2-chlorophenyl)-dimethylamino-(9H-purin-6-ylsulphanylmethyl)-3H-quinazolin-4-one;5-(2-benzyloxyethoxy)-3-(2-chlorophenyl)-2-(9H-purin-6-ylsulphanylmethyl)-3H-quinazolin-4-one;3-(2-chlorophenyl)-5-fluoro-4-oxo-3,4-dihydro-quinazolin-2-ylmethyl6-aminopurine-9-carboxylate;N-[3-(2-chlorophenyl)-5-fluoro-4-oxo-3,4-dihydro-quinazolin-2-ylmethyl]-2-(9H-purin-6-ylsulphanyl)-acetamide;2-[1-(2-fluoro-9H-purin-6-ylamino)ethyl]-5-methyl-3-o-tolyl-3H-quinazolin-4-one;5-methyl-2-[1-(9H-purin-6-ylamino)ethyl]-3-o-tolyl-3H-quinazolin-4-one;2-(6-dimethylaminopurin-9-ylmethyl)-5-methyl-3-o-tolyl-3H-quinazolin-4-one;5-methyl-2-(2-methyl-6-oxo-1.6-dihydro-purin-7-ylmethyl)-3-o-tolyl-3H-quinazolin-4-one;5-methyl-2-(2-methyl-6-oxo-1.6-dihydro-purin-9-ylmethyl)-3-o-tolyl-3H-quinazolin-4-one;2-(amino-dimethylaminopurin-9-ylmethyl)-5-methyl-3-o-tolyl-3H-quinazolin-4-one;2-(2-amino-9H-purin-6-ylsulphanylmethyl)-5-methyl-3-o-tolyl-3H-quinazolin-4-one;2-(4-amino-1,3,5-triazin-2-ylsulphanylmethyl)-5-methyl-3-o-tolyl-3H-quinazolin-4-one;5-methyl-2-(7-methyl-7H-purin-6-ylsulphanylmethyl)-3-o-tolyl-3H-quinazolin-4-one;5-methyl-2-(2-oxo-1,2-dihydro-pyrimidin-4-ylsulphanylmethyl)-3-o-tolyl-3H-quinazolin-4-one;5-methyl-2-purin-7-ylmethyl-3-o-tolyl-3H-quinazolin-4-one;5-methyl-2-purin-9-ylmethyl-3-o-tolyl-3H-quinazolin-4-one;5-methyl-2-(9-methyl-9H-purin-6-ylsulphanylmethyl)-3-o-tolyl-3H-quinazolin-4-one;2-(2,6-diamino-pyrimidin-4-ylsulphanylmethyl)-5-methyl-3-o-tolyl-3H-quinazolin-4-one;5-methyl-2-(5-methyl-[1,2,4]triazolo[1.5-a]pyrimidin-7-ylsulphanylmethyl)-3-o-tolyl-3H-quinazolin-4-one;5-methyl-2-(2-methylsulphanyl-9H-purin-6-ylsulphanylmethyl)-3-o-tolyl-3H-quinazolin-4-one;2-(2-hydroxy-9H-purin-6-ylsulphanylmethyl)-5-methyl-3-o-tolyl-3H-quinazolin-4-one;5-methyl-2-(1-methyl-1H-imidazol-2-ylsulphanylmethyl)-3-o-tolyl-3H-quinazolin-4-one;5-methyl-3-0-tolyl-2-(H-[1,2,4]triazol-3-ylsulphanylmethyl)-3H-quinazolin-4-one;2-(2-amino-6-chloro-purin-9-ylmethyl)-5-methyl-3-o-tolyl-3H-quinazolin-4-one;2-(6-aminopurin-7-ylmethyl)-5-methyl-3-o-tolyl-3H-quinazolin-4-one;2-(7-amino-1,2,3-triazolo[4,5-d]pyrimidin-3-yl-methyl)-5-methyl-3-o-tolyl-3H-quinazolin-4-one;2-(7-amino-1,2,3-triazolo[4,5-d]pyrimidin-1-yl-methyl)-5-methyl-3-o-tolyl-3H-quinazolin-4-one;2-(6-amino-9H-purin-2-ylsulphanylmethyl)-5-methyl-3-o-tolyl-3H-quinazolin-4-one;2-(2-amino-6-ethylamino-pyrimidin-4-ylsulphanylmethyl)-5-methyl-3-o-tolyl-3H-quinazolin-4-one;2-(3-amino-5-methylsulphanyl-1,2,4-triazol-1-yl-methyl)-5-methyl-3-o-tolyl-3Hquinazolin-4-one;2-(5-amino-3-methylsulphanyl-1,2,4-triazol-1-ylmethyl)-5-methyl-3-o-tolyl-3H-quinazolin-4-one;5-methyl-2-(6-methylaminopurin-9-ylmethyl)-3-o-tolyl-3H-quinazolin-4-one;2-(6-benzylaminopurin-9-yl methyl)-5-methyl-3-o-tolyl-3H-quinazolin-4-one;2-(2,6-diaminopurin-9-ylmethyl)-5-methyl-3-o-tolyl-3H-quinazolin-4-one;5-methyl-2-(9H-purin-6-ylsulphanylmethyl)-3-o-tolyl-3H-quinazolin-4-one;3-isobutyl-5-methyl-2-(9H-purin-6-ylsulphanylmethyl)-3H-quinazolin-4-one;N-{2-[5-methyl-4-oxo-2-(9H-purin-6-ylsulphanylmethyl)-4H-quinazolin-3-yl]-phenyl}-acetamide;5-methyl-3-(E-methyl-cyclohexyl)-2-(9H-purin-6-ylsulphanylmethyl)-3H-quinazolin-4-one;2-[5-methyl-4-oxo-2-(9H-purin-6-ylsulphanylmethyl)-4H-quinazolin-3-yl]-benzoicacid;3-{2-[(2-dimethylaminoethyl)methylamino]phenyl}-5-methyl-2-(9H-purin-6-yl-sulphanylmethyl)-3H-quin-azolin-4-one;3-(2-chlorophenyl)-5-methoxy-2-(9H-purin-6-ylsulphanylmethyl)-3H-quinazolin-4-one;3-(2-chlorophenyl)-5-(2-morpholin-4-yl-ethylamino)-2-(9H-purin-6-ylsulphanylmethyl)-3H-quinazolin-4-one;3-benzyl-5-methoxy-2-(9H-purin-6-ylsulphanylmethyl)-3H-quinazolin-4-one;2-(6-aminopurin-9-ylmethyl)-3-(2-benzyloxyphenyl)-5-methyl-3H-quinazolin-4-one;2-(6-aminopurin-9-ylmethyl)-3-(2-hydroxyphenyl)-5-methyl-3H-quinazolin-4-one;2-(1-(2-amino-9H-purin-6-ylamino)ethyl)-5-methyl-3-o-tolyl-3H-quinazolin-4-one;5-methyl-2-[1-(9H-purin-6-ylamino)propyl]-3-o-tolyl-3H-quinazolin-4-one;2-(1-(2-fluoro-9H-purin-6-ylamino)propyl)-5-methyl-3-o-tolyl-3H-quinazolin-4-one;2-(1-(2-amino-9H-purin-6-ylamino)propyl)-5-methyl-3-o-tolyl-3H-quinazolin-4-one;2-(2-benzyloxy-1-(9H-purin-6-ylamino)ethyl)-5-methyl-3-o-tolyl-3H-quinazolin-4-one;2-(6-aminopurin-9-ylmethyl)-5-methyl-3-{2-(2-(1-methylpyrrolidin-2-yl)-ethoxy)-phenyl}-3H-quinazolin-4-one;2-(6-aminopurin-9-ylmethyl)-3-(2-(3-dimethylamino-propoxy)-phenyl)-5-methyl-3H-quinazolin-4-one;2-(6-aminopurin-9-ylmethyl)-5-methyl-3-(2-prop-2-ynyloxyphenyl)-3H-quinazolin-4-one;2-(2-(1-(6-aminopurin-9-ylmethyl)-5-methyl-4-oxo-4H-quinazolin-3-yl]-phenoxy}-acetamide;5-chloro-3-(3,5-difluoro-phenyl)-2-[1-(9H-purin-6-ylamino)-propyl]-3H-quinazolin-4-one;3-phenyl-2-[1-(9H-purin-6-ylamino)-propyl]-3H-quinazolin-4-one;5-fluoro-3-phenyl-2-[1-(9H-purin-6-ylamino)-propyl]-3H-quinazolin-4-one;3-(2,6-difluoro-phenyl)-5-methyl-2-[1-(9H-purin-6-ylamino)-propyl]-3H-quinazolin-4-one;6-fluoro-3-phenyl-2-[1-(9H-purin-6-ylamino)-ethyl]-3H-quinazolin-4-one;3-(3,5-difluoro-phenyl)-5-methyl-2-[1-(9H-purin-6-ylamino)-ethyl]-3H-quinazolin-4-one;5-fluoro-3-phenyl-2-[1-(9H-purin-6-ylamino)-ethyl]-3H-quinazolin-4-one;3-(2.3-difluoro-phenyl)-5-methyl-2-[1-(9H-purin-6-ylamino)-ethyl]-3H-quinazolin-4-one;5-methyl-3-phenyl-2-[1-(9H-purin-6-ylamino)-ethyl]-3H-quinazolin-4-one;3-(3-chloro-phenyl)-5-methyl-2-[1-(9H-purin-6-ylamino)-ethyl]-3H-quinazolin-4-one;5-methyl-3-phenyl-2-[(9H-purin-6-ylamino)-methyl]-3H-quinazolin-4-one;2-[(2-amino-9H-purin-6-ylamino)-methyl]-3-(3,5-difluoro-phenyl)-5-methyl-3H-quinazolin-4-one;3-{2-[(2]-diethylamino-ethyl)-methyl-amino]-phenyl)-5-methyl-2-[(9H-purin-6-ylamino)-methyl]-3H-quinazolin-4-one;5-chloro-3-(2-fluoro-phenyl)-2-[(9H-purin-6-ylamino)-methyl]-3H-quinazolin-4-one;5-chloro-2-[(9H-purin-6-ylamino)-methyl]-3-o-tolyl-3H-quinazolin-4-one;5-chloro-3-(2-chloro-phenyl)-2-[(9H-purin-6-ylamino)-methyl]-3H-quinazolin-4-one;6-fluoro-3-(3-fluoro-phenyl)-2-[1-(9H-purin-6-ylamino)-ethyl]-3H-quinazolin-4-one;2-[1-(2-amino-9H-purin-6-ylamino)-ethyl]-5-chloro-3-(3-fluoro-phenyl)-3H-quinazolin-4-one;and the pharmaceutically acceptable salts and solvates thereof.

Formulations

The compounds according to the invention may be administered by oral,transdermal, inhalative, parenteral or sublingual route. The compoundsaccording to the invention are present as active ingredients inconventional preparations, for example in compositions consistingessentially of an inert pharmaceutical carrier and an effective dose ofthe active substance, such as for example tablets, coated tablets,capsules, lozenges, powders, solutions, suspensions, emulsions, syrups,suppositories, transdermal systems etc. An effective dose of thecompounds according to the invention is between 0.1 and 5000, preferablybetween 1 and 500, more preferably between 5-300 mg/dose for oraladministration, and between 0.001 and 50, preferably between 0.1 and 10mg/dose for intravenous. subcutaneous or intramuscular administration.For inhalation, according to the invention, solutions containing 0.01 to1.0, preferably 0.1 to 0.5% active substance are suitable. Foradministration by inhalation the use of powders, ethanolic or aqueoussolutions is preferred. It is also possible to use the compoundsaccording to the invention as a solution for infusion, preferably in aphysiological saline or nutrient saline solution.

The compounds according to the invention may be used on their own or inconjunction with other active substances according to the invention,optionally also in conjunction with other pharmacologically activesubstances. Suitable formulations include, for example, tablets,capsules, suppositories, solutions, syrups, emulsions or dispersiblepowders. Corresponding tablets may be obtained for example by mixing theactive substance(s) with known excipients, for example inert diluents,such as calcium carbonate, calcium phosphate or lactose, disintegrantssuch as maize starch or alginic acid, binders such as starch orgelatine, lubricants such as magnesium stearate or talc and/or agentsfor delaying release, such as carboxymethyl cellulose, cellulose acetatephthalate, or polyvinyl acetate. The tablets may also comprise severallayers.

Coated tablets may be prepared accordingly by coating cores producedanalogously to the tablets with substances normally used for tabletcoatings, for example collidone or shellac, gum arabic, talc, titaniumdioxide or sugar. To achieve delayed release or preventincompatibilities the core may also consist of a number of layers.Similarly the tablet coating may consist of a number of layers toachieve delayed release, possibly using the excipients mentioned abovefor the tablets.

Syrups containing the active substances or combinations thereofaccording to the invention may additionally contain a sweetener such assaccharine, cyclamate, glycerol or sugar and a flavour enhancer, e.g. aflavouring such as vanillin or orange extract. They may also containsuspension adjuvants or thickeners such as sodium carboxymethylcellulose, wetting agents such as, for example, condensation products offatty alcohols with ethylene oxide, or preservatives such asp-hydroxybenzoates.

Solutions for injection are prepared in the usual way, e.g. with theaddition of preservatives such as p-hydroxybenzoates, or stabiliserssuch as alkali metal salts of ethylenediamine tetraacetic acid, andtransferred into injection vials or ampoules.

Capsules containing one or more active substances or combinations ofactive substances may for example be prepared by mixing the activesubstances with inert carriers such as lactose or sorbitol and packingthem into gelatine capsules.

Suitable suppositories may be made for example by mixing with carriersprovided for this purpose, such as neutral fats or polyethyleneglycol orthe derivatives thereof.

A therapeutically effective daily dose is between 1 and 2000 mg,preferably 10-500 mg per adult.

The Examples which follow illustrate the present invention withoutrestricting its scope:

Examples of Pharmaceutical Formulations

A) Tablets per tablet active substance 100 mg lactose 140 mg maizestarch 240 mg polyvinylpyrrolidone  15 mg magnesium stearate  5 mg 500mg

The finely ground active substance, lactose and some of the corn starchare mixed together. The mixture is screened, then moistened with asolution of polyvinylpyrrolidone in water, kneaded, granulated while wetand dried. The granulate, the rest of the corn starch and the magnesiumstearate are screened and mixed together. The mixture is compressed toform tablets of a suitable shape and size.

B) Tablets per tablet active substance 80 mg corn starch 190 mg  lactose55 mg microcrystalline cellulose 35 mg polyvinylpyrrolidone 15 mgsodium-carboxymethyl starch 23 mg magnesium stearate  2 mg 400 mg 

The finely ground active substance, some of the corn starch, lactose,microcrystalline cellulose and polyvinylpyrrolidone are mixed together,the mixture is screened and worked with the remaining corn starch andwater to form a granulate which is dried and screened. Thesodium-carboxymethyl starch and the magnesium stearate are added andmixed in and the mixture is compressed to form tablets of a suitablesize.

C) Coated tablets per coated tablet Active substance  5 mg Corn starch41.5 mg   Lactose 30 mg Polyvinylpyrrolidone  3 mg Magnesium stearate0.5 mg  80 mg

The active substance, corn starch, lactose and polyvinylpyrrolidone arethoroughly mixed and moistened with water. The moist mass is pushedthrough a screen with a 1 mm mesh size, dried at about 45° C. and thegranules are then passed through the same screen. After the magnesiumstearate has been mixed in, convex tablet cores with a diameter of 6 mmare compressed in a tablet-making machine. The tablet cores thusproduced are coated in a known manner with a covering consistingessentially of sugar and talc. The finished coated tablets are polishedwith wax

D) Capsules per capsule Active substance  50 mg Corn starch 268.5 mg  Magnesium stearate  1.5 mg 320 mg

The substance and corn starch are mixed and moistened with water. Themoist mass is screened and dried. The dry granules are screened andmixed with magnesium stearate. The finished mixture is packed into size1 hard gelatine capsules.

E) Ampoule solution active substance 50 mg sodium chloride 50 mg waterfor inj. 5 ml

The active substance is dissolved in water at its own pH or optionallyat pH 5.5 to 6.5 and sodium chloride is added to make it isotonic. Thesolution obtained is filtered free from pyrogens and the filtrate istransferred under aseptic conditions into ampoules which are thensterilised and sealed by fusion. The ampoules contain 5 mg, 25 mg and 50mg of active substance.

F) Suppositories Active substance  50 mg Solid fat 1650 mg 1700 mg

The hard fat is melted. At 40° C. the ground active substance ishomogeneously dispersed. It is cooled to 38° C. and poured into slightlychilled suppository moulds.

G) Oral suspension active substance 50 mg hydroxyethylcellulose 50 mgsorbic acid 5 mg sorbitol (70%) 600 mg glycerol 200 mg flavouring 15 mgwater ad 5 ml

Distilled water is heated to 70° C. Hydroxyethyl-cellulose is dissolvedtherein with stirring. After the addition of sorbitol solution andglycerol the mixture is cooled to ambient temperature. At ambienttemperature, sorbic acid, flavouring and substance are added. Toeliminate air from the suspension it is evacuated with stirring.

1. A process of preparing a compound of the formula (I),

wherein A denotes CH or N, n denotes 1, 2, 3 or 4, R¹ denotes hydrogenor a group, optionally substituted, consisting of C₁₋₄-alkyl, OR^(1.1)and NR^(1.1.1)R^(1.1.2); R^(1.1), R^(1.2) which may be identical ordifferent, denote H or C₁₋₄-alkyl; or NR^(1.1)R^(1.2) denotes a 5- to6-membered heterocycle, optionally containing a further N atom; R² whichmay be identical or different, denote hydrogen or a group selected fromamong F, Cl, Br, I, CN, CF₃, CF₂H, CFH₂ and NH₂; or a group, optionallysubstituted, selected from among —O—C₁₋₄-alkyl, C₁₋₄-alkyl andC₂₋₆-alkenyl; R⁴ denotes hydrogen, OH, NH₂, or a group, optionallysubstituted, selected from among C₁₋₆-alkyl, C₂₋₆-alkenyl,C₃₋₆-cycloalkyl, —N(C₁₋₄-alkyl)₂ and —NH(C₁₋₄-alkyl); R³ denotes a groupselected from among:

wherein X denotes a group, optionally substituted, selected from amongC₁₋₆-alkylene, C₂₋₆-alkenylene, C₁₋₆-alkynylene, C₃₋₇-cycloalkylene,C₆₋₇-cycloalkenylene and —C₁₋₄-alkylene-C₃₋₇-cycloalkylene; Y denotes abond or X; R⁵, R⁶, R⁷ which may be identical or different, denotehydrogen or a group, optionally substituted, selected from amongC₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₁₋₆-haloalkyl, C₃₋₈-cycloalkyl,C₃₋₈-cycloalkenyl, C₃₋₇-cycloalkyl-C₁₋₄-alkyl, aryl, heteroaryl, spiro,heterocycloalkyl, aryl-C₁₋₆-alkyl, heteroaryl-C₁₋₆-alkyl andheterocycloalkyl-C₁₋₆-alkyl, or NR⁶R⁷ form a five-, six- orseven-membered ring consisting of carbon atoms and optionally anitrogen, oxygen or sulphur atom as further heteroatoms or a ringselected from among:

R^(5.1) which may be identical or different, denote hydrogen or a groupselected from among C₁₋₆-alkyl, C₃₋₈-cycloalkyl, —CO—C₁₋₃-alkyl andCONH₂; or R⁵ and R⁶ together form a saturated or unsaturated alkylenebridge which is optionally substituted and may optionally contain afurther nitrogen, oxygen or sulphur atom; or R³ is

x, y which may be identical or different denote 0, 1, 2, 3, 4 or 5; Wdenotes O, NR⁹ or CR⁹R¹⁰; R⁸ denotes H, OR^(8.1), NR^(8.1)R^(8.2) oroptionally substituted C₁₋₆-alkyl; R^(8.1), R^(8.2) which may beidentical or different, denote hydrogen, COR^(8.1.1),CONR^(8.1.1)R^(8.1.2), SO₂NR^(8.1.1)R^(8.1.2) or SO₂R^(8.1.1) or agroup, optionally substituted, selected from among C₁₋₆-alkyl,C₃₋₆-alkenyl, C₃₋₆-alkynyl, C₃₋₈-cycloalkyl andC₃₋₇-cycloalkyl-C₁₋₄-alkyl, or NR^(8.1)R^(8.2) together form a five-,six- or seven-membered ring which may optionally contain a furtherheteroatom; R^(8.1.1), R^(8.1.2) which may be identical or different,denote hydrogen or a group, optionally substituted, selected from amongC₁₋₆-alkyl, C₃₋₈-cycloalkyl and C₃₋₇-cycloalkyl-C₁₋₄-alkyl, orNR^(8.1.1)R^(8.1.2) together form a five- or six-membered ring, whichmay optionally contain a further heteroatom; R⁹, R¹⁰ which may beidentical or different, denote a group, optionally substituted by OMe,CN, F, Cl or Br, selected from among C₁₋₆-alkyl, C₂₋₆-alkenyl,C₂₋₆-alkynyl, C₃₋₈-cycloalkyl, C₃₋₈-cycloalkenyl,C₃₋₇-cycloalkyl-C₁₋₄-alkyl, aryl, heteroaryl, spiro, heterocycloalkyl,(aryl-C₁₋₆-alkyl-) and heteroaryl-C₆₋₁₀-alkyl (heteroaryl-C₁₋₆-alkyl);or R⁹, R¹⁰, which may be identical or different, denote hydrogen,COR^(9.1), CONR^(9.1)R^(9.2), SO₂R^(9.1) or SO₂NR^(9.1)R^(9.2); R^(9.1),R^(9.2) which may be identical or different, denote hydrogen or anoptionally substituted group selected from among C₁₋₆-alkyl,C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₁₋₆-haloalkyl, C₃₋₈-cycloalkyl,C₃₋₇-cycloalkyl-C₁₋₄-alkyl, aryl, heteroaryl, spiro, heterocycloalkyl,aryl-C₁₋₆-alkyl- and heteroaryl-C₁₋₆-alkyl-; or NR^(9.1)R^(9.2) togetherform a five- or six-membered ring, which may optionally contain afurther heteroatom, comprising (a) reacting a compound of formula (II)

wherein R¹ has the meaning specified, with a compound of formula

wherein R⁴ has the specified meaning and Ag denotes a leaving group, and(b) reacting the compound of general formula (III)

resulting from step (a), wherein R¹ and R⁴ have the meanings specified,with a compound of general formula

wherein R² and n have the meanings specified and B denotes a leavinggroup, and (c) reacting a compound of general formula (IV)

resulting from step (b), wherein R¹, R², R⁴ and n have the meaningsspecified and B denotes a leaving group, with a compound of generalformula

wherein R³ has the specified meaning.
 2. A compound of the formula (II),

wherein R¹ denotes hydrogen or a group, optionally substituted,consisting of C₁₋₄-alkyl, OR^(1.1) and NR^(1.1)R^(1.2); R^(1.1), R^(1.2)which may be identical or different, denote H or C₁₋₄-alkyl; orNR^(1.1)R^(1.2) denotes a 5- to 6-membered heterocycle, optionallycontaining a further N atom; optionally in the form of thepharmacologically acceptable acid addition salts thereof.
 3. A compoundof the formula (III),

wherein R¹ denotes hydrogen or a group, optionally substituted,consisting of C₁₋₄-alkyl, OR^(1.1) and NR^(1.1)R^(1.2); R^(1.1), R^(1.2)which may be identical or different, denote H or C₁₋₄-alkyl; orNR^(1.1)R^(1.2) denotes a 5- to 6-membered heterocycle, optionallycontaining a further N atom; R⁴ denotes hydrogen, OH, NH₂, or a group,optionally substituted, selected from among C₁₋₆-alkyl, C₂₋₆-alkenyl,C₃₋₆-cycloalkyl, —N(C₁₋₄-alkyl)₂ and —NH(C₁₋₄-alkyl); optionally in theform of the pharmacologically acceptable acid addition salts thereof.